View PDF VersionPrevious ArticleNext Article

Open Access Article
This Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence
DOI: 10.1039/D2RA01791A (Review Article) RSC Adv., 2022, 12, 19171-19208

A comprehensive review on phytochemistry and pharmacology of genus Kopsia: monoterpene alkaloids – major secondary metabolites

Nguyen Quang Hopa and Ninh The Son*bc
aFaculty of Chemistry, Hanoi Pedagogical University 2 (HPU2), Nguyen Van Linh, Xuanhoa, Phucyen, Vinhphuc, Vietnam
bInstitute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Caugiay, Hanoi, Vietnam. E-mail: yamantson@gmail.com; ntson@ich.vast.vn
cGraduate University of Science and Technology, VAST, Vietnam

Received 19th March 2022 , Accepted 21st June 2022

First published on 5th July 2022

Abstract

Kopsia belongs to the family Apocynaceae, which was originally classified as a genus in 1823. Kopsia consists of medicinal plants that can be traditionally used to treat rheumatoid arthritis, pharyngitis, tonsillitis, and dropsy. More than one hundred and twenty-five publications have been documented relating to the phytochemical and pharmacological results, but a systematic review is not available. The goal of this study is to compile almost all of the secondary metabolites from the plants of genus Kopsia, as well as the coverage of their pharmacological research. The document findings were conducted via reliable sources, including Web of Science, Sci-Finder, Science Direct, PubMed, Google Scholar, and publishers, while four words “Kopsia”, “monoterpene alkaloids”, “Phytochemistry” and “Pharmacology” are key factors to search for references. Most Kopsia secondary metabolites were collected. A total of four hundred and seventy-two, including four hundred and sixty-six monoterpene alkaloids, five triterpenoids, and one sterol, were summarized, along with their resource. Kopsia monoterpene alkaloids presented in various skeletons, but aspidofractinines, eburnamines, and chanofruticosinates are the three major backbones. Mersinines and pauciflorines are new chemical classes of monoterpene alkaloids. With the rich content of monoterpene alkaloids, Kopsia constituents were also the main objects in pharmacological studies since the plant extracts and isolated compounds were proposed for anti-microbial, anti-inflammatory, anti-allergic, anti-diabetic, anti-manic, anti-nociceptive, acetylcholinesterase (AChE) inhibitory, cardiovascular, and vasorelaxant activities, especially cytotoxicity.

1. Introduction

Natural products are chemical substances created by living organisms and found in nature. In the medicinal chemistry field, this concept is usually limited to secondary metabolites.1 The pharmacological studies on potential bioactive agents tend to find that lead molecules for drug development could arise from natural resources.

Kopsia belongs to the subfamily Rauvolfioideae of the family Apocynaceae.2 This genus, containing about 30 species, is widely distributed in Southeast Asia, China, Australia, and some islands of the Western Pacific.3,4 Kopsia plants are recognized as a fertile reservoir of novel and bioactive secondary metabolite type alkaloids. Therefore, they have been traditionally used in each country. Chinese folk medicine deals with the use of parts of K. officinalis Tsiang & P. T. Li to treat rheumatoid arthritis, pharyngitis, tonsillitis, and dropsy.4 In Malaysia, the roots of four species, K. larutensis King & Gamble, K. macrophylla Hook.f., K. singapurensis Ridl., and K. paucifora Hook.f., were applied as a poultice to ulcerate noses in tertiary syphilis.2,5 Kopsia constituents are also well-known in pharmacological discoveries, in which they have a wide spectrum of pharmacological effects such as anticancer and anti-manic activities.6,7

Recently, the search for bioactive molecules from the genus Kopsia has drawn lots of interest to natural product chemists and pharmacists.8–13 Although there have been a variety of experimental studies, an overview of phytochemical and pharmacological assessments is not available now. The current review provides notes on basic knowledge about phytochemical research and sheds light on the pivotal role of Kopsia constituents in pharmacological examinations. More than one hundred twenty-five relevant publications have been used, as well as the data collection is from the 1950s to now.

2. Phytochemistry

Since the 1950s, a large number of phytochemical studies on Kopsia plants have been published. To some extent, this current paper provides basic knowledge about the isolation processes of Kopsia secondary metabolites. The results related to experimental reports are primarily based on chromatographic approaches, such as silica gel chromatography or HPLC procedure (high performance chromatography column), whereas the NMR structural elucidation of isolated compounds is due to the most utilization of spectral methods, such as 1D/2D-NMR, mass spectroscopy (MS), ultraviolet-visible (UV-Vis), optical rotation (OR), infrared (IR), circular dichroism (CD) and comparisons with previous literature. Among recorded thirty species, nineteen plants, including K. arborea, K. dasyrachis, K. deverrei, K. flavida, K. fruticosa, K. grandifolia, K. griffithii, K. hainanensis, K. jasminiflora, K. lancibracteolata, K. lapidilecta, K. larutensis, K. macrophylla, K. officinalis, K. pauciflora, K. profunda, K. singapurensis, K. teoi, and K. terengganensis, have been most widely utilized for phytochemical investigations. More than four hundred seventy metabolites were collected and tabulated in Table 1 and Fig. 1–9. Significantly, four hundred sixty-six isolated compounds have been categorized as monoterpene alkaloids, in which they have induced a diversity of chemical skeletons, including aspidofractinines 1–204, chanofruticosinates 205–241, aspidospermines 242–248, danuphyllines 249–252, eburnamines 253–301, akuammilines 302–322, sarpagines 323–326, aspidophyllines 327–331, strychnos 332–356, stemmadenine 357, mersinines 358–378, pauciflorines 379–390, skytanthines 391–400, rhazinilams 401–409, lundurines 410–426, aspidospermas 427–431, catharinensines 432–436, leuconoxines 437–442, pericines 443–446, alstonines 447–449, quebrachamines 450–452, arbophyllinines 453–454, arboflorines 455–456, andrasinines 457–458, corynantheines 459–460, carbolines 461–462, arbophyllidine 463, mersicarpine 464, azepane-fused tetrahydro-β-carboline 465, and andranginine 466. In each group, the name of the compound was alphabetically ordered in an arrangement. The similar chemical classes will be placed close to each other.
Table 1 Monoterpene alkaloids and non-alkaloidal constituents from the genus Kopsia
No. Compounds Species References
Aspidofractinines
1 Arbolodinine A K. arborea stem bark 8
2 Aspidofractinine K. arborea stem bark, K. hainanensis twig and leaf, K. officinalis stem 9–11
3 (2β,5β)-Aspidofractinin-16-ol K. hainanensis twig and leaf, K. officinalis leaf 9, 12 and 13
4 Aspidofractinine-1,3-dicarboxylic acid K. officinalis stem 11
5 N-Carbomethoxy-11-hydroxy-12-methoxykopsinaline K. griffithii leaf, K. officinalis twig, leaf and fruit 14–16
6 N-Carbomethoxy-11-methoxy-12-hydroxykopsinaline K. officinalis fruit 14
7 N(1)-Carbomethoxy-11, 12-dimethoxykopsinaline K. griffithii leaf, K. officinalis fruit 14, 15 and 17
8 N-Carbomethoxy-12-methoxykopsinaline K. officinalis fruit 14
9 N-Carbomethoxy-5,22-dioxokopsane K. dasyrachis stem, K. pauciflora stem 18 and 19
10 Dasyrachine K. arborea stem bark, K. dasyrachis stem 10 and 18
11 Decarbomethoxykopsine (demethoxycarbonylkopsin) K. fruticosa leaf, K. officinalis leaf and twig 16 and 20
12 Decarbomethoxyisokopsine K. fruticosa leaf 20
13 Decarbomethoxykopsifine K. arborea twig, K. dasyrachis stem, K. officinalis stem, K. pauciflora stem and stem bark 11, 18, 19, 21 and 22
14 N(1)-Decarbomethoxykopsamine K. arborea stem bark, K. hainanensis stem and leaf, K. pauciflora leaf, K. singapurensis leaf 7, 10, 22 and 23
15 Na-Demethoxycarbonyl-12-methoxykopsine K. jasminiflora stem bark, K. officinalis leaf and twig 16, 24 and 25
16 10-Demethoxykopsidasinine K. jasminiflora 26
17 5,22-Dioxokopsane K. hainanensis stem bark and twig, K. macrophylla bark, K. officinalis root, stem, twig and fruit, K. pauciflora stem bark 11, 12, 14, 16, 19 and 27–29
18 11,12-Dimethoxykopsamine K. dasyrachis leaf 30
19 11,12-Dimethoxykopsinaline K. pauciflora stem bark 22
20 16-epi-Kopsinine K. fruticosa stem bark, K. officinalis stem, K. singapurensis leaf 11, 31 and 32
21 16-epi-Kopsinilam K. jasminiflora stem bark 24
22 16-epi-17α-Hydroxy-Δ14,15-kopsinine K. teoi stem bark and leaf 33
23 14,15-β-Epoxykopsingine K. teoi leaf 34
24 N(1)-Formylkopsininic acid K. singapurensis root 35 and 36
25 N(1)-Formylkopsininic acid-N(4)-oxide K. singapurensis root 35 and 36
26 Fruticosamine K. fruticosa leaf, K. jasminiflora leaf 20 and 37–41
27 Fruticosiamine A K. fruticosa leaf 41
28 Fruticosine K. jasminiflora leaf, K. fruticosa leaf, K. officinalis twig 20 and 37–42
29 11-Hydroxykopsilongine K. officinalis fruit and leaf 13 and 25
30 11-Hydroxykopsingine K. teoi leaf 34
31 5β-Hydroxykopsinine K. jasminiflora stem bark 24
32 15-Hydroxykopsamine K. singapurensis root 35 and 36
33 15α-Hydroxykopsinine K. arborea stem bark; K. fruticosa leaf and stem bark, K. singapurensis bark 10, 31 and 36
34 17α-Hydroxykopsinine K. teoi stem bark 43
35 17α-Hydroxy-Δ14,15-kopsinine K. singapurensis stem bark and leaf; K. teoi stem and stem bark 23, 32, 34 and 44–48
36 Jasminiflorine K. jasminiflora leaf 40
37 Kopsamidine A K. arborea stem bark 10
38 Kopsamidine B K. arborea stem bark 10
39 Kopsamine K. arborea twig and stem bark, K. dasyrachis stem and leaf, K. officinalis stem, root, leaf and fruit, K. griffithii leaf, K. pauciflora stem and stem bark, K. singapurensis leaf and root, K. teoi stem bark 10, 13–15, 17–19, 21, 25, 30, 36, 43, 49 and 50
40 Kopsamine N-oxide K. arborea stem bark; K. dasyrachis stem and leaf, K. officinalis fruit, K. griffithii leaf, K. pauciflora stem, K. singapurensis root 10, 14, 15, 17–19, 30, 36, 49 and 51
41 Kopsanone K. arborea stem bark; K. fruticosa stem bark, K. jasminiflora stem bark, K. hainanensis stem bark, K. pauciflora stem and stem bark, K. officinalis fruit 10, 14, 19, 22, 24, 29 and 31
42 Kopsaporine K. singapurensis stem bark, K. teoi stem and stem bark 32, 34, 44 and 45
43 Kopsiafrutine A K. fruticosa aerial part 52
44 Kopsiafrutine B K. fruticosa aerial part 52
45 Kopsiafrutine C K. fruticosa aerial part 52
46 Kopsiafrutine D K. fruticosa aerial part 52
47 Kopsiafrutine E K. fruticosa aerial part 52
48 Kopsiahainanin A K. hainanensis twig and leaf 53
49 Kopsiahainanin B K. hainanensis twig and leaf 53
50 Kopsiahainanin C K. hainanensis twig and leaf 53
51 Kopsiahainanin D K. hainanensis twig and leaf 53
52 Kopsiahainanin E K. hainanensis twig and leaf 53
53 Kopsiahainanin F K. hainanensis twig and leaf 53
54 Kopsiahainin A K. hainanensis twig and leaf 54
55 Kopsiahainin B K. hainanensis twig and leaf 54
56 Kopsiahainin C K. hainanensis twig and leaf 54
57 Kopsiahainin D K. hainanensis twig and leaf 54
58 Kopsiahainin E K. hainanensis twig and leaf 54
59 Kopsiaofficine A K. officinalis aerial part 55
60 Kopsiaofficine B K. officinalis aerial part 55
61 Kopsiaofficine C K. officinalis aerial part 55
62 Kopsiarborines A K. arborea aerial part 56
63 Kopsidarine K. singapurensis leaf 48
64 Kopsidasine K. dasyrachis leaf 57
65 Kopsidasine-N-oxide K. dasyrachis leaf 57
66 Kopsidasinine K. dasyrachis leaf 57
67 Kopsidine A K. singapurensis leaf, K. teoi leaf and stem bark 34, 43, 45, 48 and 58
68 Kopsidine B K. teoi leaf 34, 45 and 58
69 Kopsidine C K. singapurensis leaf, K. teoi leaf 34, 48 and 58
70 Kopsidine C N-oxide K. singapurensis leaf 48
71 Kopsidine D K. singapurensis leaf, K. teoi leaf 32, 34 and 58
72 Kopsidine E K. arborea bark 59
73 Kopsifine K. arborea stem bark, K. dasyrachis stem, K. hainanensis twig, K. officinalis stem, K. pauciflora stem and stem bark, K. singapurensis root 10–12, 18, 22, 49 and 60
74 Kopsiflorine K. arborea stem bark; K. dasyrachis stem, K. hainanensis stem and leaf, K. officinalis leaf 7, 10, 12, 13, 18 and 61
75 Kopsiflorine N(4)-oxide K. dasyrachis stem 18
76 Kopsifoline A K. fruticosa leaf and aerial part, K. singapurensis leaf 31, 36, 52, 62 and 63
77 Kopsifoline B K. fruticosa leaf 31, 62 and 63
78 Kopsifoline C K. fruticosa leaf 31, 62 and 63
79 Kopsifoline D K. fruticosa leaf 31 and 63
80 Kopsifoline E K. fruticosa leaf 31 and 63
81 Kopsifoline F K. fruticosa leaf 31 and 63
82 Kopsifoline G K. hainanensis stem 64
83 Kopsihainin B K. hainanensis stem 65
84 Kopsihainin C K. hainanensis stem 65
85 Kopsihainin D K. hainanensis twig 12
86 Kopsihainin E K. hainanensis twig 12
87 Kopsihainin F K. hainanensis twig 12
88 Kopsijasminine K. teoi stem bark 43
89 Kopsijasmine K. jasminiflora leaf 40
90 Kopsilarutensinine K. larutensis stem bark and leaf 66
91 Kopsilongine K. arborea twig and stem bark, K. dasyrachis stem, K. griffithii leaf and stem bark, K. officinalis leaf, K. pauciflora stem 10, 13, 15, 17–19, 21, 22 and 32
K. singapurensis leaf
92 Kopsilongine-N-oxide K. singapurensis leaf 32
93 Kopsiloscine A K. singapurensis leaf 32
94 Kopsiloscine B K. singapurensis leaf 32
95 Kopsiloscine C K. singapurensis leaf and stem bark 32 and 48
96 Kopsiloscine D K. singapurensis leaf 32
97 Kopsiloscine E K. singapurensis leaf 32
98 Kopsiloscine F K. singapurensis leaf 32
99 Kopsiloscine G K. singapurensis stem bark and leaf 23 and 48
100 Kopsiloscine H K. singapurensis stem bark 23
101 Kopsiloscine I K. hainanensis stem and leaf, K. singapurensis stem bark 7 and 23
102 Kopsiloscine J K. singapurensis leaf 23
103 Kopsimaline A K. singapurensis leaf 23
104 Kopsimaline B K. singapurensis leaf 23
105 Kopsimaline C K. singapurensis leaf 23
106 Kopsimaline D K. singapurensis leaf 23
107 Kopsimaline E K. singapurensis leaf 23
108 Kopsimaline F K. singapurensis leaf 48
109 Kopsinarine K. dasyrachis stem, K. hainanensis twig 12 and 18
110 Kopsine K. dasyrachis stem, K. fruticosa leaf 18, 20, 38, 39, 41 and 67
111 Kopsinganol K. singapurensis stem bark, K. teoi stem, stem bark and leaf 32, 34, 43, 45, 47 and 48
112 Kopsingine K. singapurensis leaf and stem bark, K. teoi stem, stem bark and leaf 32–34, 44, 45 and 48
113 Kopsinginine K. teoi stem and stem bark 34, 43–45 and 47
114 Kopsinginol K. teoi stem and stem bark 34, 45 and 47
115 Kopsinidine A K. arborea stem bark 10
116 Kopsinidine B K. arborea stem bark 10
117 Kopsininic acid (kopsinic acid) K. hainanensis stem bark, K. jasminiflora stem bark, K. officinalis stem, twig and leaf, K. singapurensis bark and leaf 11, 13, 16, 24, 29 and 36
118 Kopsinicine K. singapurensis leaf 23
119 Kopsinidine A K. arborea stem bark, K. officinalis leaf 10 and 25
120 Kopsinidine B K. arborea stem bark, K. officinalis leaf 10 and 25
121 Kopsinidine C K. officinalis leaf and twig 16
122 Kopsinidine D K. officinalis leaf and twig 16
123 Kopsinidine E K. officinalis leaf and twig 16
124 Kopsinilam K. hainanensis stem bark and twig, K. jasminiflora stem bark, K. officinalis stem, twig, leaf and fruit 11, 12, 14, 16, 24 and 29
125 Kopisininate K. hainanensis stem and leaf 7
126 Kopsinine K. arborea twig and stem bark, K. dasyrachis stem, K. fruticosa stem bark, K. jasminiflora stem bark, K. grandifolia stem bark, K. griffithii leaf and stem bark, K. hainanensis leaf, stem, stem bark and twig, K. larutensis stem, stem bark and leaf, K. officinalis root, stem, twig, leaf and fruit, K. singapurensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, K. teoi stem bark 7, 9–11, 13–19, 21–25, 28, 29, 32, 36, 42, 43, 48, 50, 51, 64–66 and 68–72
127 Kopsinine-N(4)-oxide K. dasyrachis stem, K. griffithii stem bark, K. hainanensis stem and leaf, K. officinalis fruit and leaf, K. pauciflora stem, K. singapurensis bark 7, 13, 15, 18, 25 and 36
128 Kopsinine methochloride K. officinalis leaf and twig 16
129 Kopsinine B K. officinalis leaf and twig 16
130 Kopsinine F K. hainanensis stem and leaf 7
131 Kopsinitarine A K. singapurensis leaf, K. teoi leaf 34, 48, 73 and 74
132 Kopsinitarine B K. singapurensis leaf, K. teoi leaf 34, 48, 73 and 74
133 Kopsinitarine C K. teoi leaf 34, 73 and 74
134 Kopsinitarine D K. teoi leaf 34 and 74
135 Kopsinitarine E K. teoi stem bark 43
136 Kopsinol K. teoi stem and stem bark 34, 45 and 47
137 (−)-Kopsinoline K. hainanensis stem bark, K. officinalis stem, twig and leaf 11, 16 and 29
138 Kopsiofficine A K. officinalis stem 11
139 Kopsiofficine B K. officinalis stem 11
140 Kopsiofficine C K. officinalis stem 11
141 Kopsiofficine D K. officinalis stem 11
142 Kopsiofficine E K. officinalis stem 11
143 Kopsiofficine F K. officinalis stem 11
144 Kopsiofficine L K. officinalis stem 75
145 Kopsofinone K. singapurensis leaf 23
146 Kopsonoline K. teoi stem bark 43
147 Kopsorinine K. fruticosa leaf and stem bark 31
148 Lahadinine A K. pauciflora leaf 76
149 Lahadinine B K. pauciflora leaf 76
150 Mersingine A K. singapurensis leaf, K. teoi leaf 34, 49 and 74
151 Mersingine B K. teoi leaf 34 and 74
152 N(1)-Methoxycarbonyl-11,12-dimethoxykopsinaline K. arborea stem bark, K. pauciflora stem 10, 19 and 51
153 N(1)-Methoxycarbonyl-11,12-methoxylenedioxykopsinaline K. officinalis leaf, twig, stem and root, K. pauciflora stem and leaf 11, 16, 42, 51, 69 and 76
154 N(1)-Methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine K. profunda stem 4
155 N(1)-Methoxycarbonyl-12-methoxy-Δ16,17-kopsinine K. griffithii leaf, K. pauciflora stem, K. profunda stem and leaf, K. teoi stem bark 4, 17, 19, 43, 51 and 77
156 N(1)-Methoxycarbonyl-12-methoxykopsinaline K. officinalis root, stem, twig, leaf and fruit, K. pauciflora stem 11, 16, 25, 51 and 69
157 N(1)-Methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine N(4) oxide K. profunda stem and leaf 77
158 N(1)-Methoxycarbonyl-12-hydroxy-Δ16,17-kopsinine K. pauciflora stem, K. profunda stem and leaf 19 and 77
159 N(1)-Methoxycarbonyl-12-methoxy-Δ16,17-kopsinine N(4) oxide K. profunda stem and leaf 77
160 11-Methoxykopsingine K. teoi leaf 34
161 11-Methoxykopsilongine K. dasyrachis stem, K. officinalis stem and leaf 11, 13 and 18
162 11-Methoxykopsilongine N(4)-oxide K. dasyrachis stem 18
163 11-Methoxy-12-hydroxy-kopsinol K. teoi leaf 34
164 12-Methoxykopsidasinine K. griffithii leaf 17
165 (−)-12-Methoxykopsinaline K. officinalis leaf and twig 13, 16, 42 and 69
166 12-Methoxykopsine K. arborea leaf, K. jasminiflora stem bark, K. officinalis root and stem, K. pauciflora leaf 11, 22, 24 and 78
167 12-Methoxy-10-demethoxykopsidasinine K. griffithii leaf, K. pauciflora stem 15, 51
168 12-Methoxypleiocarpine K. dasyrachis stem and leaf, K. hainanensis stem and leaf, K. griffithii leaf, K. pauciflora stem 7, 15, 17–19 and 30
169 (−)-Methylenedioxy-11,12-kopsinaline K. arborea twig 7
170 N(4)-Methylkopsininate K. officinalis leaf and twig 16
171 11,12-Methylenedioxykopsaporine K. singapurensis bark, K. teoi stem, stem bark and leaf 33, 34 and 79
172 (−)-11,12-Methylenedioxykopsinaline K. dasyrachis stem, K. officinalis root, stem, leaf, twig and fruit 11, 16, 18, 25 and 69
173 11,12-Methylenedioxykopsinaline N(4)-oxide K. griffithii stem bark, K. officinalis stem, twig and leaf 11, 15 and 16
174 11,12-Methylenedioxykopsine K. arborea stem bark, K. dasyrachis stem, K. officinalis stem, K. pauciflora stem bark 10, 11, 18 and 22
175 Nitaphylline K. teoi leaf 34, 46 and 80
176 5-Oxokopsinic acid K. jasminiflora stem bark, K. officinalis twig and leaf 16 and 24
177 Paucidactine A K. pauciflora stem bark 19
178 Paucidactine B K. arborea stem bark, K. pauciflora stem bark 10 and 19
179 Paucidactine C K. arborea stem bark, K. pauciflora stem bark 10 and 19
180 Paucidactine D K. pauciflora stem bark 19
181 Paucidactine E K. pauciflora stem bark 19
182 Paucidactinine K. pauciflora stem bark 19
183 Paucidisine K. pauciflora stem bark 19
184 Paucidirinine K. pauciflora stem bark 19
185 Paucidirisine K. pauciflora stem bark 19
186 Pauciduridine K. officinalis stem, K. pauciflora stem bark 11 and 19
187 Paucifinine K. pauciflora leaf and stem bark 22 and 76
188 Paucifinine-N-oxide K. pauciflora leaf 76
189 Pleiocarpine K. arborea stem bark, K. dasyrachis stem and leaf, K. griffithii leaf, K. officinalis fruit, K. pauciflora stem, 10, 14, 15, 17–19, 25 and 30
190 Pleiocarpine N-oxide K. pauciflora stem 19
191 Pseudokopsinine K. pauciflora leaf and stem bark 22
192 5,6-Secokopsinine K. jasminiflora stem bark 24
193 Singaporentine A K. singapurensis leaf 36
194 Singapurensine A K. singapurensis bark 79
195 Singapurensine B K. singapurensis bark 79
196 Singapurensine C K. singapurensis bark 79
197 Singapurensine D K. singapurensis bark 79
198 Venacarpine A K. fruticosa leaf, K. singapurensis bark 31 and 36
199 Venacarpine B K. fruticosa leaf 31
200 Venalstonidine K. arborea stem bark 10
201 (−)-Venalstonine K. arborea stem bark, K. fruticosa stem bark, K. lapidilecta stem and bark, K. singapurensis bark 10, 31, 36 and 81
202 Yunnanoffine A K. officinalis leaf 25
203 Yunnanoffine B K. officinalis leaf 25
204 Yunnanoffine D K. officinalis leaf 25
[thin space (1/6-em)]
Chanofruticosinates
205 Chanofruticosinic acid K. officinalis leaf and twig 16
206 N1-Decarbomethoxy chanofruticosinic acid K. hainanensis stem and leaf 7
207 11,12-Dimethoxydanuphylline K. fruticosa aerial part 3
208 Flavisiamine A (prunifoline D) K. arborea leaf, K. flavida leaf 82–84
209 Flavisiamine B K. flavida leaf 83
210 Flavisiamine C K. arborea leaf, K. flavida leaf 83 and 84
211 Flavisiamine D (prunifoline E) K. arborea leaf and stem bark, K. flavida leaf 10 and 82–84
212 Flavisiamine E K. flavida leaf 41
213 Flavisiamine F K. flavida leaf 41
214 12-Hydroxylprunifoline A K. lancibracteolata stem 85
215 12-Hydroxylprunifoline C K. lancibracteolata stem 85
216 Kopreasin A K. arborea leaf 84
217 Kopsia A (methyl chanofruticosinate) K. dasyrachis leaf, K. hainanensis stem and leaf, K. officinalis leaf, twig, and stem, K. pauciflora leaf 7, 13, 16, 22, 25, 30, 75 and 86
218 Kopsia B (des-N-(methoxycarbonyl)chanofruticosin-methyleste) K. officinalis leaf 86
219 Kopsia C (6,7-methylendioxychanofruticosin-methylester or methyl 11,12-methylenedioxychanofruticosinate) K. arborea leaf and stem bark, K. dasyrachis leaf, K. officinalis stem and leaf, twig and leaf, K. pauciflora stem bark and leaf 10, 16, 22, 30, 75, 84, 86 and 87
220 Kopsihainanine A K. hainanensis leaf and stem 6
221 Kopsihainanine B K. hainanensis leaf and stem 6
222 12-Methoxychanofruticosinic acid K. officinalis leaf and twig 16
223 Methyl chanofruticosinate N(4)-oxide K. hainanensis stem and leaf 7
224 Methyl 11,12-dimethoxychanofruticosinate K. arborea leaf, K. flavida leaf, K. officinalis leaf 13, 22, 25, 82, 88 and 89
225 Methyl N1-decarbomethoxychanofruticosinate K. arborea leaf and stem bark, K. dasyrachis leaf, K. flavida leaf, K. fruticosa leaf, K. hainanensis stem and leaf, K. officinalis twig, leaf and stem, K. pauciflora leaf 7, 10, 16, 25, 30, 41, 42, 65, 75, 82–84 and 87
226 Methyl N1-decarbomethoxy chanofruticosinate N(4)-oxide K. hainanensis stem and leaf 7
227 Methyl 12-methoxy-N1-decarbomethoxychanofruticosinate K. arborea leaf, K. flavida leaf 83, 84, 88 and 89
228 Methyl 12-methoxychanofruticosinate K. arborea leaf and stem bark, K. flavida leaf, K. officinalis stem, twig and leaf, K. pauciflora leaf 10, 16, 22, 75, 82, 84, 88 and 89
229 Methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate K. arborea stem bark and leaf, K. dasyrachis leaf, K. flavida leaf, K. officinalis leaf, twig and stem, K. pauciflora leaf and stem bark 10, 16, 22, 25, 30, 42, 75, 82–84 and 87–89
230 Methyl 11,12-methylenedioxy-N1-decarbomethoxy-Δ14,15-chanofruticosinate K. arborea stem bark and leaf, K. flavida leaf, K. hainanensis stem and leaf 7, 10, 82–84 and 87
231 Methyl (2β,11β,12β,19α)-6,7-didehydro-8,21-dioxo-11,21-cycloaspidospermidine-2-carboxylate K. officinalis leaf 13
232 Methyl 3-oxo-12-methoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate K. flavida leaf 89
233 Methyl 3-oxo-11,12-methylenedioxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate K. flavida leaf 89
234 Δ1,2-Methyldemethoxycarbonylchanofruticosinate K. officinalis leaf 25
235 11,12-Methylenedioxychanofruticosinic acid K. officinalis leaf and twig 16
236 3-Oxo-11,12-dimethoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate K. fruticosa aerial part 3
237 N(4)-Oxide prunifoline D K. lancibracteolata stem 85
238 Prunifoline A K. arborea leaf 82
239 Prunifoline B K. arborea leaf 82 and 84
240 Prunifoline C K. arborea leaf, K. fruticosa leaf 41 and 82
241 Prunifoline F K. arborea leaf 82
[thin space (1/6-em)]
Aspidospermines
242 Aspidospermine K. pauciflora leaf 22
243 (+)-1,2-Dehydroaspidospermine K. pauciflora leaf 22
244 Eburenine K. arborea aerial part 90
245 Kopsiofficine G K. officinalis stem 11
246 Kopsiyunnanine G K. arborea aerial part 90
247 Vincadifformine K. arborea twig and stem bark, K. officinalis stem and fruit 10, 11, 14 and 21
248 Vincadifformine N(4)-oxide K. officinalis stem 11
[thin space (1/6-em)]
Danuphyllines
249 Danuphylline K. dasyrachis leaf 30 and 91
250 Danuphylline B K. arborea leaf 78
251 11,12-De(methylenedioxy)danuphylline K. officinalis leaf 13
252 Kopsihainin A K. hainanensis stem 65
[thin space (1/6-em)]
Eburnamines
253 (−)-Demethylnorpleiomutine K. dasyrachis stem, K. pauciflora stem 18 and 19
254 (+)-Eburnamenine K. pauciflora stem and stem bark 19 and 22
255 (−)-Eburnamenine K. arborea aerial part, K. hainanensis twig, stem bark and leaf, K. larutensis bark, K. officinalis fruit 9, 14, 29, 90 and 70
256 (+)-Eburnamine K. hainanensis stem bark 29
257 (−)-Eburnamine K. arborea aerial part, K. griffithii stem bark, K. hainanensis twig and leaf, K. larutensis leaf, stem and stem bark, K. officinalis root and stem, K. pauciflora stem and stem bark, K. singapurensis stem bark, K. terengganensis bark 5, 9, 15, 19, 22, 23, 50, 51, 66, 68, 70, 90 and 92
258 (−)-Eburnaminol K. larutensis stem bark, K. terengganensis bark 68 and 92
259 (+)-Eburnamonine K. arborea aerial part, K. dasyrachis stem, K. griffithii leaf, K. larutensis leaf and stem bark, K. officinalis leaf and twig, K. pauciflora stem 5, 13, 15, 17–19, 42, 51, 68, 70, 90 and 93
260 (+)-Eburnamonine N(4)-oxide K. larutensis leaf and stem 5 and 70
261 (−)-Eburnamonine K. jasminiflora stem bark 24
262 (−)-O-Ethyleburnamine K. arborea aerial part, K. larutensis stem 70 and 90
263 (+)-Ethylisoeburnamine K. arborea aerial part 90
264 16α-Hydroxy-19-oxoeburnamine K. officinalis leaf 25
265 16β-Hydroxy-19-oxoeburnamine K. officinalis leaf 25
266 (+)-19(R)-Hydroxyeburnamine K. dasyrachis stem 18 and 93
267 19-Hydroxy-(−)-eburnamonine K. arborea twig, K. larutensis leaf, K. officinalis twig 5, 7 and 42
268 (−)-19(R)-Hydroxyisoeburnamine K. dasyrachis stem, K. pauciflora stem and stem bark 19, 22 and 93
269 (+)-(19R)-19-Hydroxyeburnamine K. officinalis leaf, K. pauciflora stem and stem bark 13, 19 and 22
270 (−)-19(R)-Hydroxyeburnamenine K. pauciflora stem 19
271 (−)-(19R)-19-Hydroxyisoeburnamine K. dasyrachis stem, K. officinalis leaf 13 and 18
272 (−)-19(R)-Hydroxy-O-ethylisoeburnamine K. pauciflora stem 19
273 19(S)-Hydroxy-Δ14-vicamone K. jasminiflora stem bark 24
274 (+)-Isoeburnamine K. arborea aerial part, K. dasyrachis stem, K. hainanensis stem bark, K. larutensis leaf, stem and stem bark, K. teoi stem bark and leaf, K. officinalis leaf, K. pauciflora stem and stem bark, K. terengganensis bark 5, 13, 18, 19, 22, 33, 29, 51, 68, 70, 90, 92 and 93
275 (−)-Isoeburnamine K. officinalis root 28 and 69
276 16-Isoeburnamine ((+)-methylisoeburnamine) K. arborea aerial part, K. officinalis stem 75 and 90
277 (+)-Kopsoffine K. hainanensis, K. officinalis root 28 and 29
278 Kopsiofficine H K. officinalis stem 75
279 Kopsiofficine I K. officinalis stem 75
280 Kopsiofficine J K. officinalis stem 75
281 Kopsiofficine K K. officinalis stem 75
282 Kopsoffinol K. dasyrachis stem, K. pauciflora stem 19 and 93
283 (+)-Larutensine K. larutensis stem bark 68
284 Larutenine K. larutensis leaf and stem, K. officinalis leaf, K. pauciflora leaf, K. terengganensis bark 5, 13, 22, 70 and 92
285 Larutenine A K. pauciflora stem, stem bark and leaf 19 and 22
286 Larutenine B K. pauciflora stem and stem bark 19 and 22
287 Melohenine B K. hainanensis twig and leaf 9
288 (−)-Methyleburnamine K. arborea aerial part 90
289 (−)-Norpleiomutine K. dasyrachis stem, K. macrophylla bark, K. pauciflora stem and stem bark 18, 19, 22, 27 and 51
290 (+)-O-Methyleburnamine K. officinalis stem 75
291 (−)-O-Methylisoeburnamine (O-methylvincanol) K. hainanensis twig and leaf, K. officinalis stem 9 and 75
292 (+)-19-Oxoeburnamine K. pauciflora stem and stem bark 19, 22 and 51
293 19-Oxo-(−)-eburnamonine K. jasminiflora stem bark, K. officinalis twig 24 and 42
294 (−)-19-Oxoisoeburnamine K. pauciflora stem 19
295 O-Methyl-16-epi-vincanol K. hainanensis twig and leaf 9
296 20-Oxo-eburnamenine K. officinalis root, leaf and stem 25, 50 and 75
297 Phutdonginin K. arborea twig 21
298 Terengganensine A K. terengganensis bark 92
299 Terengganensine B K. terengganensis bark 92
300 Δ14-Vicamone K. jasminiflora stem bark 24
301 Yunnanoffine C K. officinalis leaf 25
[thin space (1/6-em)]
Akuammilines
302 Akuammidine K. arborea stem bark, K. singapurensis root, stem bark and leaf 10, 23, 32, 48 and 49
303 Akuammiline K. macrophylla bark, K. teoi stem and stem bark 27, 34, 43, 45 and 47
304 Akuammiline N(4)-oxide K. griffithii stem bark 15
305 ψ-Akuammigine K. fruticosa stem bark 31
306 Deacetylakuammiline (rhazimol) K. deverrei stem bark, K. griffithii leaf and stem bark, K. macrophylla bark, K. singapurensis stem bark, K. teoi stem and stem bark 15, 17, 23, 27, 34, 45, 47 and 94
307 Dregamine K. macrophylla bark 27
308 16-epi-akuammiline K. singapurensis leaf, stem bark and root, K. teoi stem bark 23, 32, 36, 43 and 48
309 16-epi-deacetylakuammiline K. deverrei stem bark, K. griffithii stem bark, K. fruticosa stem bark, K. singapurensis bark, stem bark and leaf, K. teoi stem and stem bark 15, 23, 31, 32, 34, 36, 43, 48 and 94
310 16-epi-deacetylakuammiline-N(4)-oxide K. griffithii stem bark, K. singapurensis bark 15 and 36
311 16-Hydroxymethyl-pleiocarpamine K. deverrei stem bark, K. fruticosa stem bark, K. singapurensis stem bark and bark, K. teoi stem bark 23, 31, 43, 36 and 94
312 N-Methylpleiocarpamine K. singapurensis root 36
313 5-Methoxystrictamine K. hainanensis twig and leaf 9
314 Rhazimal K. arborea stem bark 10
315 Rhazinaline N(4)-oxide K. griffithii stem bark 15
316 Rhazinoline K. arborea stem bark 10
317 Picralinal K. hainanensis twig and leaf 9
318 Picramicine K. fruticosa stem bark, K. singapurensis stem bark 23 and 31
319 Pleiocarpamine K. dasyrachis stem, K. deverrei stem bark, K. fruticosa stem bark, K. singapurensis bark, K. teoi stem bark 18, 31, 36, 43 and 94
320 Pleiocarpamine methochloride K. officinalis leaf and twig 16
321 Pleiomalicine K. hainanensis twig and leaf 9
322 Singaporentinidine K. singapurensis root 35 and 36
[thin space (1/6-em)]
Sarpagines
323 10-Hydroxy-vincadiffine K. hainanensis twig and leaf 9
324 Perivine K. officinalis root and stem 50
325 Tabernaemontanine K. macrophylla bark 27
326 Vincadiffine K. hainanensis twig and leaf 9
[thin space (1/6-em)]
Aspidophyllines
327 Aspidodasycarpine K. singapurensis root and stem bark, K. teoi stem and stem bark 23, 32, 34, 36, 43, 48 and 49
328 Aspidophylline A K. singapurensis stem bark 32
329 Aspidophylline B K. singapurensis stem bark 48
330 Lonicerine K. fruticosa stem bark, K. singapurensis bark and stem bark, K. teoi stem, stem bark and leaf 23, 31–34, 36, 43 and 48
331 Vincophylline K. singapurensis leaf 32
[thin space (1/6-em)]
Strychnoses
332 Akuammicine K. pauciflora leaf 22
333 Arbolodinine B K. arborea stem bark 8
334 Arbolodinine C K. arborea stem bark 8
335 (E)-Condylocarpine K. arborea aerial part, K. pauciflora leaf 22 and 95
336 (E)-Condylocarpine N-oxide K. arborea aerial part 95
337 14α-Hydroxycondylocarpine K. deverri stem bark, K. singapurensis stem bark 23 and 94
338 14α-Hydroxy-N(4)-methylcondylocarpine K. singapurensis root 35 and 36
339 14(S)-Hydroxy-19(R)-methoxytubotaiwine K. jasminiflora stem bark 24
340 Isocondylocarpine K. arborea aerial part 95
341 Isocondylocarpine N-oxide K. arborea aerial part 95
342 Kopsiyunnanine A K. arborea aerial part, K. officinalis aerial part 96 and 97
343 Kopsiyunnanine I K. arborea aerial part 98 and 99
344 Kopsiyunnanine J1 K. arborea aerial part 99 and 100
345 Kopsiyunnanine J2 K. arborea aerial part 99 and 100
346 Kopsiyunnanine L K. arborea aerial part 101 and 102
347 Kopsiyunnanine M K. arborea aerial part 101 and 102
348 Kopsiyunnanine F1 K. arborea aerial part 95
349 Kopsiyunnanine F2 K. arborea aerial part 95
350 Kopsiyunnanine F3 K. arborea aerial part 95
351 Leuconicine B K. arborea aerial part 98
352 19(R)-Methoxytubotaiwine K. arborea aerial part and stem bark, K. jasminiflora stem bark 10, 24 and 95
353 19(S)-Methoxytubotaiwine K. arborea aerial part and stem bark, K. hainanensis twig 10, 12 and 95
354 Mossambine K. singapurensis stem bark 23
355 Precondylocarpine K. pauciflora leaf 22
356 Tubotaiwine K. arborea aerial part, K. hainanensis stem and stem bark 29, 64 and 95
[thin space (1/6-em)]
Stemmadenine
357 Stemmadenine K. pauciflora leaf 22
[thin space (1/6-em)]
Mersinines
358 Mersidasine A K. singapurensis leaf 103
359 Mersidasine B K. singapurensis leaf 103
360 Mersidasine C K. singapurensis leaf 103
361 Mersidasine D K. singapurensis leaf 103
362 Mersidasine E K. singapurensis leaf 103
363 Mersidasine F K. singapurensis leaf 103
364 Mersidasine G K. singapurensis leaf 103
365 Mersifoline A K. singapurensis leaf 103
366 Mersifoline B K. singapurensis leaf 103
367 Mersifoline C K. singapurensis leaf 103
368 Mersilongine K. singapurensis leaf 23 and 104
369 Mersiloscine K. singapurensis leaf 103 and 105
370 Mersiloscine A K. singapurensis leaf 103
371 Mersiloscine B K. singapurensis leaf 103
372 Mersinaline K. singapurensis leaf 23 and 106
373 Mersinine A K. fruticosa leaf, K. singapurensis leaf 103 and 105, 107
374 Mersinine B K. singapurensis leaf 103 and 105
375 Mersinine C K. singapurensis leaf 103
376 Mersiphyllines A K. singapurensis leaf 108
377 Mersiphyllines B K. singapurensis leaf 108
378 Mersirachine K. singapurensis leaf 23 and 106
[thin space (1/6-em)]
Pauciflorines
379 11,12-Demethoxy-16-deoxypauciflorine K. officinalis stem and leaf 109
380 20-Deoxykopsijasminilam K. jasminiflora leaf 40
381 Kopsiarborines C K. arborea aerial part 56
382 Kopsijasminilam K. jasminiflora leaf 40
383 Δ14-Kopsijasminilam K. jasminiflora leaf 40
384 Kopsioffine A K. officinalis stem and leaf 109
385 Kopsioffine B K. officinalis stem and leaf 109
386 Kopsioffine C K. officinalis stem and leaf 109
387 Pauciflorine A K. pauciflora leaf 110
388 Pauciflorine B K. pauciflora leaf 110
389 Pauciflorine C K. pauciflora leaf 22
390 Paucifoline K. pauciflora leaf 22
[thin space (1/6-em)]
Skytanthines
391 Kinabalurine A (kinabalurine) K. pauciflora leaf 111 and 112
392 Kinabalurine B K. pauciflora leaf 112
393 Kinabalurine C K. pauciflora leaf 112
394 Kinabalurine D K. pauciflora leaf 112
395 Kinabalurine E K. pauciflora leaf 112
396 Kinabalurine F K. pauciflora leaf 112
397 Kinabalurine G K. dasyrachis leaf 30
398 Kopsilactone K. macrophylla bark 27
399 Kopsirachine K. dasyrachis leaf 30 and 113
400 Kopsone K. macrophylla bark 27
[thin space (1/6-em)]
Rhazinilams
401 5,21-Dihydrorhazinilam K. arborea stem bark, K. singapurensis stem bark and leaf 10, 23 and 48
402 Kopsiyunnanine C1 K. arborea aerial part, K. officinalis aerial part 96 and 114
403 Kopsiyunnanine C2 K. arborea aerial part, K. officinalis aerial part 96 and 114
404 Kopsiyunnanine C3 K. arborea aerial part, K. officinalis aerial part 96 and 114
405 Leuconolam K. griffithii leaf and stem bark, K. hainanensis twigs, stems and leaves, K. officinalis leaf, K. pauciflora leaf, K. singapurensis stem bark 7, 9, 12, 15, 17, 22, 23, 25 and 32
406 O-Methylleuconolam K. arborea stem bark, K. hainanensis twig, K. officinalis stem 10, 12 and 87
407 Rhazinal K. dasyrachis stem 32
408 Rhazinicine K. arborea stem bark, K. dasyrachis stem, K. singapurensis root 10, 18, 49 and 60
409 Rhazinilam K. arborea aerial part and stem bark, K. officinalis leaves and twigs, K. pauciflora leaves and stem bark, K. singapurensis leaf, bark and stem bark, K. teoi stem, stem bark and leaf 16, 13, 22, 23, 25, 32–34, 36, 45, 47, 48 and 114
[thin space (1/6-em)]
Lundurines
410 Epilapidilectinol K. lapidilecta stem and bark 81
411 Grandilodine A K. grandifolia stem bark 72
412 Grandilodine B K. grandifolia stem bark 72
413 Grandilodine C K. grandifolia leaf 72
414 Isolapidilectine A K. grandifolia leaf, K. lapidilecta stem and bark 72 and 81
415 Lapidilectam K. grandifolia stem bark, K. lapidilecta stem and bark 72 and 81
416 Lapidilectine A K. grandifolia stem bark, K. lapidilecta bark, stem and leaf 72 and 115
417 Lapidilectine B K. grandifolia stem bark, K. lapidilecta bark, stem and leaf 72 and 115
418 Lapidilectinol K. lapidilecta stem and bark 81
419 Lundurine A K. tenuis leaf 71
420 Lundurine B K. tenuis leaf 71
421 Lundurine C K. tenuis leaf 71
422 Lundurine D K. tenuis leaf 71
423 Tenuisine A K. tenuis leaf 116 and 117
424 Tenuisine B K. tenuis leaf 71, 116 and 117
425 Tenuisine C K. tenuis leaf 71, 116 and 117
426 Tenuiphylline K. tenuis leaf 71 and 117
[thin space (1/6-em)]
Aspidospermas
427 Buchtienine K. griffithii leaf and stem bark 15 and 17
428 Corynantheol K. hainanensis twig and leaf 9
429 19,20-Dihydroisositsirikine K. officinalis stem 75
430 Dihydrocorynantheol K. hainanensis twig and leaf 9
431 16(R)-19,20-E-Isositsirikine K. griffithii leaf, K. pauciflora leaf 15, 17 and 22
[thin space (1/6-em)]
Catharinensines
432 Catharinensine K. pauciflora leaf 22
433 Kopsirensine A K. pauciflora leaf 22
434 Kopsirensine B K. pauciflora leaf 22
435 Kopsirensine C K. pauciflora leaf 22
436 Kopsiyunnanine B K. arborea aerial part, K. officinalis aerial part 96 and 97
[thin space (1/6-em)]
Leuconoxines
437 Arboloscine K. arborea stem bark 10 and 118
438 Arboloscine A K. pauciflora leaf 22
439 Leuconodine D K. officinalis stem 75
440 Leuconodine F (6-oxoleuconoxine) K. griffithii leaf, K. pauciflora leaf 22 and 43
441 Leuconoxine K. arborea stem bark, K. griffithii leaf and stem bark, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark, K. teoi stem bark 15, 17, 19, 22, 23 and 43
442 Melodinine E K. arborea twig 21
[thin space (1/6-em)]
Pericines
443 Pericidine K. arborea stem bark 10 and 118
444 Pericine K. arborea stem bark 10
445 Pericine N-oxide K. arborea stem bark 10
446 Valparicine K. arborea stem bark 119 and 120
[thin space (1/6-em)]
Alstonines
447 Oxayohimban-16-carboxy acid K. officinalis stem 75
448 (−)-Tetrahydroalstonine K. arborea stem bark, K. dasyrachis stem, K. griffithii leaf, K. officinalis root, twigs and leaves, K. larutensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark; K. teoi stem bark 10, 15, 17–19, 23, 25, 32, 42, 43, 66 and 69
449 Tetrahydroalstonine pseudoindoxyl K. pauciflora leaf 22
[thin space (1/6-em)]
Quebrachamines
450 Kopsiyunnanine D K. arborea aerial part 114
451 Kopsiyunnanine H K. arborea aerial part 90
452 (−)-Quebrachamine K. arborea aerial part, K. hainanensis twig and leaf, K. officinalis root, K. pauciflora leaf 9, 22, 69 and 114
[thin space (1/6-em)]
Arbophyllinines
453 Arbophyllinine A K. arborea bark 59
454 Arbophyllinine B K. arborea bark 59
[thin space (1/6-em)]
Arboflorines
455 Arboflorine K. arborea stem bark 10
456 Kopsiyunnanine E K. arborea aerial part, K. officinalis aerial part 96, 99 and 121
[thin space (1/6-em)]
Andrasinines
457 Andransinine K. pauciflora leaf 22
458 Andransinine A K. pauciflora leaf 22
[thin space (1/6-em)]
Corynantheines
459 Arboricine K. arborea leaf and stem bark 10 and 120
460 Arboricinine K. arborea leaf and stem bark 10 and 120
[thin space (1/6-em)]
Carbolines
461 Harmane K. griffithii leaf and stem 15 and 17
462 Harmicine K. griffithii leaf 15 and 17
[thin space (1/6-em)]
Arbophyllidine
463 Arbophyllidine K. arborea stem bark 59
[thin space (1/6-em)]
Mersicarpine
464 Mersicarpine K. arborea stem bark, K. pauciflora leaf, K. singapurensis stem bark 10, 22 and 23
[thin space (1/6-em)]
Azepane-fused tetrahydro-β-carboline
465 Kopsiyunnanine K K. arborea aerial part 102
[thin space (1/6-em)]
Andranginine
466 Andranginine K. arborea aerial part 102
[thin space (1/6-em)]
Triterpenoids and sterols
467 β-Amyrin K. singapurensis leaf and bark 122
468 β-Amyrin acetate K. singapurensis leaf and bark 122
469 β-Amyrone K. singapurensis leaf and bark 122
470 Lupeol K. singapurensis leaf and bark 122
471 Lupeol acetate K. singapurensis leaf and bark 122
472 Stigmasterol K. singapurensis leaf and bark 122

2.1. Aspidofractinines

Aspidofractinines are the largest phytochemical class of isolated alkaloids from the genus Kopsia. As shown in Table 1, more than two hundred aspidofractinines have been isolated to date, and they derive from various parts of K. arborea, K. dasyrachis, K. fruticosa, K. grandifolia, K. griffithii, K. hainanensis, K. hainanensis, K. jasminiflora, K. larutensis, K. macrophylla, K. officinalis, K. pauciflora, K. profunda, K. singapurensis, and K. teoi.4,7–59,61–79,81 From Fig. 1, Kopsia aspidofractinines 1–204 occurred in both monomer and dimer forms, but they did not bind to sugar units. Aspidofractinines 1–204 have been generally associated with the esterification at nitrogen N-1 and carbon C-16, carbonylation at carbon C-5, expoxydation at carbons C-11 and C-12, and hydroxylation, or methoxylation at carbons C-11, C-12, C-16, C-17, and C-18. It was found that 5,22-dioxokopsane (17), kopsamine (39), kopsamine N-oxide (40), kopsanone (41), kopsifine (73), kopsilongine (91), kopsininic acid (117), kopsinilam (124), kopsinine (126), kopsinine-N(4)-oxide (127), pleiocarpine (189), and (−)-venalstonine (201) might be seen as characteristic metabolites in the group of Kopsia aspidofractinines. For instance, compound 126 was recorded to appear in K. arborea twig and stem bark, K. dasyrachis stem, K. fruticosa stem bark, K. jasminiflora stem bark, K. grandifolia stem bark, K. griffithii leaf and stem bark, K. hainanensis leaf, stem, stem bark and twig, K. larutensis stem, stem bark and leaf, K. officinalis root, stem, twig, leaf and fruit, K. singapurensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, and K. teoi stem bark, whereas its N(4)-oxide (127) presented in K. dasyrachis stem, K. griffithii stem bark, K. hainanensis stem and leaf, K. officinalis fruit and leaf, K. pauciflora stem, and K. singapurensis bark.5–7,9–11,13–19,21–25,28,29,32,36,42,43,48,51,65,66,68–72
image file: d2ra01791a-f1.tif
Fig. 1 Aspidofractinines from genus Kopsia.

Taking phytochemical studies into account, a new bisindole alkaloid arbolodinine A (1) was isolated from K. arborea stem bark.8 Based on NMR, MS, and ECD data, compound 1 was a product by the combination of two apidofractinine units, and its biosynthetic pathway was structurally formulated from precursor 126. Aspidofractinine (2) can be found in K. arborea stem bark, K. hainanensis twigs and leaves, and K. officinalis stem,9–11 but aspidofractinine-1,3-dicarboxylic acid (4) was only detected in K. officinalis stem.11 (2β,5β)-Aspidofractinin-16-ol (3) was a new 16-alcohol derivative found in K. officinalis leaves for the first time, and then was detected in K. hainanensis twigs and leaves.9,12,13 Compounds 5–9 have shared the same feature of carbomethoxylation at nitrogen N-1,14–19 in which N-carbomethoxy-11-hydroxy-12-methoxykopsinaline (5) and N-carbomethoxy-11-methoxy-12-hydroxykopsinaline (6) were two new metabolites in nature.14–16 Dasyrachine (10) containing isokopsine skeleton was one of the new metabolites present in the 95% EtOH extract of K. dasyrachis stem.18 In contrast to compounds 5–9, the next compounds decarbomethoxykopsine (11), decarbomethoxyisokopsine (12), decarbomethoxykopsifine (13), N(1)-decarbomethoxykopsamine (14), Na-demethoxycarbonyl-12-methoxykopsine (15), and 10-demethoxykopsidasinine (16) are associated with the decarbomethoxylation at nitrogen N-1.10,11,16,18–26 Among them, compounds 13, 15, and 16 were new in nature. 11,12-Dimethoxykopsamine (18) was a known metabolite found in K. dasyrachis leaves, but 11,12-dimethoxykopsinaline (19) was a new one in the stem bark of K. pauciflora stem bark.22,30 Similarly, 16-epi-kopsinine (20), 16-epi-kopsinilam (21), 16-epi-17α-hydroxy-Δ14,15-kopsinine (22), 14,15-β-epoxykopsingine (23), N(1)-formylkopsininic acid (24), N(1)-formylkopsininic acid-N(4)-oxide (25), fruticosamine (26), fruticosiamine A (27), and fruticosine (28) were new aspidofractinines, and found in genus Kopsia for the first time.11,20,24,31–37,39–42 The known metabolite 11-hydroxykopsilongine (29) has been detected in both the fruit and leaf of K. officinalis,13,25 while 11-hydroxykopsingine (30), 5β-hydroxykopsinine (31), and 15-hydroxykopsamine (32) were first isolated from polar extracts of K. teoi leaf, K. jasminiflora stem bark, and K. singapurensis root, respectively.24,34,35 Two known compounds 33 and 34 were products of 15α and 17α-hydroxylation of kopsinine, respectively (Fig. 1). In the meantime, the structure of the new metabolite 35 is closely related to kopsinine by 17α-OH and olefinic double bond at carbons C-14 and C-15.44 For a long time, Ruangrungsi et al. (1987) successfully isolated two new aspidofractinines, named jasminiflorine (36) and kopsijasmine (89), from the MeOH extract of K. jasminiflora leaves, whereas kopsamidines A–B (37–38) were separated from the acidic EtOH extract of K. arborea stem bark.10,40

To search for bioactive metabolites from Kopsia plants, Long et al. (2018) isolated five new aspidofractinines kopsiafrutines A–E (43–47) from the 80% EtOH extract of K. fruticosa aerial part.52 Eleven new analogs, kopsiahainanins A–F (48–53) and kopsiahainins A–E (54–58) were among the new compounds found in the 80% EtOH extract of K. hainanensis twigs and leaves.53,54 In another approach, chromatographic separation of the 95% EtOH extract of K. officinalis aerial part can lead to the isolation of three new metabolites (59–61), which named kopsiaofficines A–C.55 From K. arborea aerial part, the new compound kopsiarborines A (62) was isolated.56 Three new metabolites, kopsidasine (64), kopsidasine-N-oxide (65), and kopsidasinine (66) were separated from K. dasyrachis leaves and structurally confirmed by the NMR analysis and Hofmann reaction.57 Thirteen previously undescribed metabolites kopsidines A–D (67–69 and 71), kopsinitarines B–D (132–134), mersingines A–B (150–151), 11-methoxykopsingine (160), 11-methoxy-12-hydroxy-kopsinol (163), 11,12-methylenedioxykopsaporine (171), and nitaphylline (175) have further been observed in K. teoi leaf, while its stem bark also contained seven other new compounds kopsinganol (111), kopsinginine (113), kopsinginol (114), kopsinol (136), kopsinitarine E (135), kopsinol (136), and kopsonoline (146).33,34,43–45,73,74,80 Kopsidarine (63), kopsidine C N-oxide (70), and singaporentine A (193) were three new compounds existed in K. singapurensis leaf, whereas its bark encompassed four new others singapurensines A–D (194–197)36,48,58,79 In two years 2007 and 2008, primarily based on CC approach, Subramaniam et al. successfully isolated nineteen new aspidofractinines, including kopsilongine-N-oxide (92), kopsiloscines A–J (93–102), kopsinalines A–F (103–108), kopsinicine (118), and kopsofinone (145) from K. singapurensis leaf or stem bark (Table 1 and Fig. 1).23,32,48 Kopsiflorine (74) is now available in the genus Kopsia, but its N(4)-oxide (75) and kopsinarine (109) were new in nature and were found in K. dasyrachis stem.18 Six indole alkaloidal constituents kopsifolines A–F (76–81) with unprecedented hexacyclic carbon skeleton were detected in the acidic EtOH extract of K. fruticosa leaves.62,63 Kopsifoline G (82) and kopsihainins B–F (83–87) were purified as new alkaloids from the stem or twig extracts of K. hainanensis.12,64,65 Among the isolated compounds, kopsijasminine (88) and kopsilarutensinine (90) were also identified to be two new aspidofractinines derived from the stem bark of K. teoi and K. larutensis, respectively.43,66 The earliest report by Guggisberg et al. (1963) identified that kopsine (110) was a new and major component of K. fruticosa leaves, and it was then isolated frequently.18,20,38,39,41,67 In a phytochemical research on the acidic EtOH extract of K. arborea stem bark, five new aspidofractinines, kopsinidines A–B (115–116), kopsinidines A–B (119–120), and paucidactine C (179) were isolated.10

Phytochemical analysis aided by NMR structural elucidation on the CHCl3 and n-BuOH extracts of K. officinalis leaf and twig has resulted in the isolation of eight new compounds kopsinidines C–E (121–123), N(1)-methoxycarbonyl-11,12-methoxylenedioxykopsinaline (153), N(1)-methoxycarbonyl-12-methoxykopsinaline (156), N(4)-methylkopsininate (170), (−)-11,12-methylenedioxykopsinaline (172), and 5-oxokopsinic acid (176), in addition to seven known compounds kopsinilam (124), kopsinine (126), kopsinine methochloride (128), kopsinine B (129), (−)-kopsinoline (137), (−)-12-methoxykopsinaline (165), and 11,12-methylenedioxykopsinaline N(4)-oxide (173).16 Among the isolates from K. hainanensis stem and leaves, the new compound kopisininate (125) itself displayed an interesting feature since it contained a carboxylate group (δC 181.6 ppm in CD3OD).7 Besides known compounds, the application of NMR and MS tools would take a good advance in the natural product chemistry field, by which the chemical structures of seven new aspidofractinines kopsiofficines A–F and L (138–144) from K. officinalis stem and three new analogs yunnanoffines A–C (202–204) from K. officinalis leaf have been determined.11,25,75 Aspidofractinines were further observed in other Kopsia plants. For instance, apart from known compounds, five new derivatives N(1)-methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine (154), N(1)-methoxycarbonyl-12-methoxy-Δ16,17-kopsinine (155), N(1)-methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine N(4) oxide (157), N(1)-methoxycarbonyl-12-hydroxy-Δ16,17-kopsinine (158), and N(1)-methoxycarbonyl-12-methoxy-Δ16,17-kopsinine N(4) oxide (159) were characteristics of K. profunda,4,77 or lahadinines A–B (145–146), 12-methoxy-10-demethoxykopsidasinine (167), paucidactines D–E (180–181), paucidactinine (182), paucidisine (183), paucidirinine (184), paucidirisine (185), pauciduridine (186), paucifinine (187), and paucifinine-N-oxide (188) were new metabolites isolated from the parts of K. pauciflora.19,51,76

2.2. Chanofruticosinates, aspidospermines, and danuphyllines

In general, Kopsia chanofruticosinate derivatives 205–241 have established a similarity in the chemical structural skeleton with aspidofractinines (Table 1 and Fig. 2). However, fragment C-2–C-16–C-17–C-20 in aspidofractinines was replaced by a carbon bridge between C-6 and C-20 in chanofruticosinates. To date, these phytochemicals occurred in K. arborea, K. dasyrachis, K. fruticosa, K. flavida, K. hainanensis, K. lancibracteolata, K. officinalis, and K. pauciflora.3,6,7,10,13,16,22,25,30,41,42,65,75,82–89 From Table 1, kopsia A (217), kopsia C (219), methyl 11,12-dimethoxychanofruticosinate (224), methyl N1-decarbomethoxychanofruticosinate (225), methyl 12-methoxychanofruticosinate (228), methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate (229), and methyl 11,12-methylenedioxy-N1-decarbomethoxy-Δ14,15-chanofruticosinate (230) were major components in the group of Kopsia chanofruticosinates. Analyzing chemical composition further, the rich alkaloid fraction of K. officinalis leaf and twig have also contained five new derivatives, chanofruticosinic acid (205), kopsias A–C (217–219), 12-methoxychanofruticosinic acid (222), and methyl (2β,11β,12β,19α)-6,7-didehydro-8,21-dioxo-11,21-cycloaspidospermidine-2-carboxylate (231).13,16,86 According to the phytochemical report of Chen and partners, N1-decarbomethoxy chanofruticosinic acid (206), kopsihainanines A–B (220–221), methyl chanofruticosinate N(4)-oxide (223), and methyl N1-decarbomethoxy chanofruticosinate N(4)-oxide (226) were previously unrecorded compounds and found in K. hainanensis stem and leaf for the first time.6,7 The application of HPLC chromatographic procedure to the 70% EtOH extract of K. fruticosa aerial part has resulted in the isolation of two new substances, 11,12-dimethoxydanuphylline (207) and 3-oxo-11,12-dimethoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate (236).3 The MeOH extract of K. flavida leaf consisted of serial new alkaloids type chanofruticosinates flavisiamines A–F (208–213).41,83 Besides known compounds, the chromatographic isolation of the alcoholic extracts of K. arborea leaves has allowed to identify the appearance of seven new methyl chanofruticosinate alkaloids, kopreasin A (216), and prunifolines A–F (208, 211, and 238–241).82,84 Finally, three new derivatives 12-hydroxylprunifoline A (214), 12-hydroxylprunifoline A (215), and N(4)-oxide prunifoline D (3) were purified from the 70% EtOH extract of K. lancibracteolata stem.85
image file: d2ra01791a-f2.tif
Fig. 2 Chanofruticosinates, aspidospermines and danuphyllines from genus Kopsia.

Regarding aspidospermines, the acidic EtOH extract of K. pauciflora leaf contained aspidospermine (242), and its (+)-1,2-dehydro derivatives (243).22 A phytochemical report conducted by Wu et al. (2010) revealed that the MeOH extract of K. arborea aerial part was characterized by the presence of the new aspidospermine kopsiyunnanine G (246), and known compound eburenine (244).90 Similarly, new compound kopsiofficine G (245), together with two known ones, vincadifformine (247) and vincadifformine N(4)-oxide (248) represented for K. officinalis stem.11

Only four indole alkaloids danuphyllines 249–252 were found in Kopsia plants, in which danuphylline (249), danuphylline B (250), 11,12-de(methylenedioxy)danuphylline (251), and kopsihainin A (252) were separated from K. dasyrachis leaf, K. arborea leaf, K. officinalis leaf, and K. hainanensis stem, respectively (Table 1 and Fig. 2).13,30,65,78,91 All these isolates were new in nature. Similar to aspidofractinine derivatives, chanofruticosinates, aspidospermines, and danuphyllines were unique chemical classes found in the family Apocynaceae. Especially, danuphylline derivatives were only detected in Kopsia, thereby they can be used as chemical markers to recognize this genus.

2.3. Eburnamines

As can be seen from Table 1 and Fig. 3, eburnamines are also a crucial phytochemical class of the genus Kopsia. Forty-nine compounds 253–301 were isolated to date, and they were mainly derived from K. arborea, K. dasyrachis, K. griffithii, K. hainanensis, K. hainanensis, K. jasminiflora, K. larutensis, K. macrophylla, K. officinalis, K. pauciflora, K. singapurensis, K. teoi, and K. terengganensis.5,9,13–15,17–19,21–25,27–29,33,42,50,51,66,68–70,75,90,92,93 Kopsia eburnamines appeared in both monomer and dimer forms, but not to have connected with sugar units. (−)-Eburnamenine (255), (−)-eburnamine (257), (+)-eburnamonine (259), (+)-isoeburnamine (274), and larutenine (284) were isolated frequently, e.g., compound 274 was detected in K. arborea aerial part, K. dasyrachis stem, K. hainanensis stem bark, K. larutensis leaf, stem and stem bark, K. teoi stem bark and leaf, K. officinalis leaf, K. pauciflora stem and stem bark, and K. terengganensis bark.5,13,18,19,22,29,33,51,68,70,90,92,93
image file: d2ra01791a-f3.tif
Fig. 3 Eburnamines from genus Kopsia.

(−)-Demethylnorpleiomutine (253), (−)-eburnaminol (258), (−)-O-ethyleburnamine (262), 19-hydroxy-(−)-eburnamonine (267), (−)-19(R)-hydroxyisoeburnamine (268), (+)-(19R)-19-hydroxyeburnamine (269), (−)-(19R)-19-hydroxyisoeburnamine (271), (+)-kopsoffine (277), kopsoffinol (282), (−)-norpleiomutine (289), (−)-O-methylisoeburnamine (291), and 19-oxo-(−)-eburnamonine (293) were found in two or three Kopsia plants (Table 1). (+)-Eburnamenine (254), (+)-eburnamine (256), (−)-eburnamonine (261), (+)-ethylisoeburnamine (263), 16α-hydroxy-19-oxoeburnamine (264), 16β-hydroxy-19-oxoeburnamine (265), melohenine B (287), (−)-methyleburnamine (288), (+)-O-methyleburnamine (290), and O-methyl-16-epi-vincanol (295), and Δ14-vicamone (300) have never been observed in genus Kopsia before. Especially, (−)-eburnaminol (258), (+)-eburnamonine N(4)-oxide (260), (+)-19(R)-hydroxyeburnamine (266), (−)-19(R)-hydroxyisoeburnamine (268), (−)-19(R)-hydroxyeburnamenine (270), (−)-(19R)-19-hydroxyisoeburnamine (271), (−)-19(R)-hydroxy-O-ethylisoeburnamine (272), (−)-isoeburnamine (275), kopsiofficines H–K (278–281), (+)-larutensine (283), larutenine (284), larutenines A–B (285–286), (−)-norpleiomutine (289), (+)-19-oxoeburnamine (292), (−)-19-oxoisoeburnamine (294), 20-oxo-eburnamenine (296), phutdonginin (297), terengganensines A–B (298–299), and yunnanoffine C (301) were new in literature and isolated from genus Kopsia for the first time. Eburnamines is now abundant in genus Kopsia, but this chemical class was only found in the family Apocynaceae.

2.4. Akuammilines, sarpagines, and aspidophyllines

A total of twenty-one akuammilines 302–322 have been outlined in Table 1 and Fig. 4. K. arborea, K. dasyrachis, K. deverrei, K. fruticosa, K. griffithii, K. hainanensis, K. macrophylla, K. officinalis, K. singapurensis, and K. teoi were main resource of these phyto-constituents.9,10,15–17,23,27,31,32,34–36,43,45,47–49,94 Previous studies revealed that deacetylakuammiline (306), 16-epi-deacetylakuammiline (309), 16-hydroxymethyl-pleiocarpamine (311), and pleiocarpamine (319) were likely to be major akuammilines in genus Kopsia.
image file: d2ra01791a-f4.tif
Fig. 4 Akuammilines, sarpagines and aspidophyllines from genus Kopsia.

The first compound akuammidine (302) was originated from K. arborea stem bark, K. singapurensis root, stem bark, and leaves, while akuammiline (303) presented in the aerial part of K. macrophylla and K. teoi.10,23,27,32,34,43,45,47–49 Akuammiline N(4)-oxide (304) and 16-epi-deacetylakuammiline-N(4)-oxide (310) were reported to be two new derivatives, which were separated from the rich alkaloidal fraction of K. griffithii stem bark.15 ψ-Akuammigine (305), dregamine (307), N-methylpleiocarpamine (312), 5-methoxystrictamine (313), rhazimal (314), rhazinaline N(4)-oxide (315), picralinal (317), pleiocarpamine methochloride (320), and pleiomalicine (321) were isolated from genus Kopsia for the first time.9,10,15,16,27,31,36 Lastly, two new metabolites, rhazinoline (316) and singaporentinidine (322), were purified from the extracts of K. arborea stem bark, K. singapurensis root, respectively.10,35

A list of four alkaloidal sarpagines 323–326 has been updated in Table 1 and Fig. 4.9,27,50 Vincadiffine (326) was a well-known metabolite, but its 10-hydroxy derivative (323) was a new compound in the literature, and both of them were isolated from the MeOH extract of K. hainanensis.9 Perivine (324) and tabernaemontanine (325) were two known sarpagines derived from K. officinalis root and stem and K. macrophylla bark, respectively.27,50

Resemble sarpagines, aspidophylline derivatives are not available in genus Kopsia. A total of five isolates 327–331 were summarized in Table 1 and Fig. 4.23,31–34,36,43,48,49 Aspidodasycarpine (327) was recorded by various authors and was detected in K. singapurensis root and stem bark, K. teoi stem, and stem bark.23,32,34,36,43,48,49 Two new phyto constituents aspidophyllines A–B (328–329), were determined to exist in K. singapurensis stem bark, while the new analog vincophylline (331) was found in its leaves.32,48 It can be concluded that lonicerine (330) was a major component in the group of aspidophyllines because it has occurred in various Kopsia plants such as K. fruticosa stem bark, K. singapurensis bark and stem bark, and K. teoi stem, stem bark and leaf.23,31–34,36,43,48

2.5. Strychnoses

Compounds 332–357 have been fallen into the group of alkaloidal strychnos derivatives (Table 1 and Fig. 5). Similar to aspidofractinines and eburnamines, Kopsia strychnoses were presented in both mono-or dimer forms, and they were mainly sourced from K. deverri, K. hainanensis, K. jasminiflora, K. officinalis, K. pauciflora, K. singapurensis, especially K. arborea.8,10,12,22–24,29,35,36,64,94–102 Significantly, except for akuammicine (332), (E)-condylocarpine (335), (E)-condylocarpine N-oxide (336), leuconicine B (351), precondylocarpine (355), and tubotaiwine (356), the remaining compounds were new in nature.
image file: d2ra01791a-f5.tif
Fig. 5 Strychnoses and stemmadenine from genus Kopsia.

By the analysis of NMR, MS, and CD data, two isolated dimeric compounds, arbolodinines B–C (333–334), were elucidated as bulk novel strychnoses, which were derived from K. arborea stem bark.8 Compound 335 is a known compound,22,95 but its 14α-hydroxy and 14(S)-hydroxy-19(R)-methoxy derivatives 337–338 were new in the literature and first were isolated from K. deverri stem bark and K. singapurensis root, respectively.35,94 Mossambine (354) was another new strychnos found in K. singapurensis stem bark.23 K. arborea aerial part has so far distributed thirteen new compounds, isocondylocarpine (340), isocondylocarpine N-oxide (341), kopsiyunnanines A, I, J1–J2, L, M, and F1–F3 (342–350), 19(R)-methoxytubotaiwine (352), and 19(S)-methoxytubotaiwine (353).10,95–98,100,101 The well-known compound tubotaiwine (356) was characteristic of K. arborea aerial part, K. hainanensis stem and stem bark, but its 14(S)-hydroxy-19(R)-methoxy derivative 339 isolated from the MeOH extract of K. jasminiflora stem bark has been determined as a new metabolite.24,29,64,95 Stemmadenine (357) from K. pauciflora leaves was the only stemmadenine detected in the genus Kopsia.22

2.6. Mersinines and pauciflorines

Mersinines with tetracyclic quinolinic skeleton are a new subclass of monoterpenoid indole alkaloids, which were only found in the plants genus Kopsia. Kopsia mersinines 358–378 were only detected in K. singapurensis leaves and occasionally in K. fruticosa leaves (Table 1 and Fig. 6).23,103–108 Of particular interest, all these isolates were novel compounds in literature. Searching for cytotoxic agents from plants, sixteen novel mersinines, comprising of mersidasines A–G (358–364), mersifolines A–C (365–367), mersiloscine (369), mersiloscines A–B (370–371), and mersinines A–C (373–375) were isolated from the acidic EtOH extract of K. singapurensis leaf.103 Their stereochemistry was confirmed by NMR, IR, UV, and X-ray analysis. K. singapurensis leaf has further been shown to contain five novel congeners, mersilongine (368), mersinaline (372), mersiphyllines A–B (376–377), and mersirachine (378).23,106,108
image file: d2ra01791a-f6.tif
Fig. 6 Mersinines and pauciflorines from genus Kopsia.

It is similar to mersinines, Kopsia pauciflorines 379–390 have induced interest since all isolates were novel in the literature, except for 11,12-demethoxy-16-deoxypauciflorine (379). K. arborea, K. jasminiflora, K. officinalis, and K. pauciflora might be a reservoir of this chemical class.22,40,56,109,110

Besides aspidofractinines, the MeOH extract of K. jasminiflora leaf has associated with the presence of three novel pauciflorines 20-deoxykopsijasminilam (380), kopsijasminilam (382), and Δ14-kopsijasminilam (383).40 In addition to known compound 379, three novel derivatives, kopsioffines A–C (384–386) were arisen from the 95% EtOH extract of K. officinalis dried stem and leaves.109 Pauciflorines A–B (387–388) reached 0.22 and 0.03 g kg−1 in K. pauciflora leaf.110 In the meantime, two other novel compounds, pauciflorine C (389) and paucifoline (390), were minor components in the acidic EtOH extract of K. pauciflora leaves.22 It is possible to conclude that mersinines and pauciflorines could be used as chemical indicators to distinguish the genus Kopsia and other genera of the family Apocynaceae.

2.7. Skytanthines, rhazinilams, and lundurines

It is recognized that the unique chemical class of skytanthines can be arranged as a new group of alkaloids. These phytochemicals were isolated from Apocynaceae Skytanthus acutus for the first time in 1960.123 From Table 1 and Fig. 7, ten new skytanthines 391–400 have been summarized. The extracts of K. dasyrachis and K. macrophylla, especially K. pauciflora, are accompanied by the presence of this type.27,30,112,113 Two publications in 1996 and 1997 by Kam and partners successfully reported the structures of serial new skytanthines kinabalurines A–F (391–396) from K. pauciflora leaves.111,112 while their following congener kinabalurine G (397) was derived from K. dasyrachis leaf.30 Significantly, the novel alkaloidal kopsirachine (399) isolated from K. dasyrachis leaves was determined to be a hybrid compound by the combination of catechin and skytanthine.113 After being run Sephadex LH-20 and silica gel CC, a new monoterpene alkaloids containing a lactone ring, kopsilactone (398), and other new monoterpene alkaloids possessing 2-azabicyclo[3.3.1] backbone, kopsone (400), were isolated from the MeOH extract of K. macrophylla bark.27 Based on these findings, skytanthines can be seen as chemical evidence to determine the close relationship among Apocynaceae plants, especially between genera Skytanthus and Kopsia.
image file: d2ra01791a-f7.tif
Fig. 7 Skytanthines, rhazinilams and lundurines from genus Kopsia.

Rhazinilam (409) is an alkaloid discovered in the Apocynaceae plant Melodinus australis in 1965.124 It was then isolated from the shrub of the other Apocynaceae plant Rhazya stricta as well as other organisms.125 This compound was established as a main component in the group of Kopsia rhazinilams since it was found in K. arborea aerial parts and stem bark, K. officinalis leaf and twig, K. pauciflora leaf and stem bark, K. singapurensis leaf, bark and stem bark, and K. teoi stem, stem bark and leaf.13,16,22,23,25,32–34,36,45,47,48,114 Leuconolam (405) can be also seen as another main component because of its occurrence in K. griffithii leaves and stem bark, K. hainanensis twig, stem and leaf, K. officinalis leaf, K. pauciflora leaves, and K. singapurensis stem bark.7,9,12,15,17,22,23,25,32 As shown in Table 1, known compound 5,21-dihydrorhazinilam (401) existed in K. arborea stem bark and K. singapurensis stem bark and leaves.10,23,48 From Fig. 7, three new compounds, kopsiyunnanines C1–C3 (402–404), which were isolated from the aerial part of K. arborea and K. officinalis, established the same backbone with rhazinilam (409).96,114 O-Methylleuconolam (406) and rhazinal (407) were two well-known compounds, but their congener rhazinicine (408) separated from K. arborea stem bark, K. dasyrachis stem, and K. singapurensis root was a new derivative.10,12,18,32,49,60,87 To the best of our knowledge, rhazinilams were only observed in the family Apocynaceae, as well as the plants of three genus Melodinus, Rhazya, and Kopsia being the main resources.

Kopsia lundurines 410–426 have generally been formed by the combination of an indole ring and a lactam ring through an eight-ring member (Fig. 7). Notably, all of these seventeen compounds were novel in nature, and the three plants, K. lapidilecta, K. grandifolia, and K. tenuis, are the main reservoirs (Table 1).

Awang and partners also isolated and identified six novel pauciflorines, epilapidilectinol (410), isolapidilectine A (414), lapidilectam (415), lapidilectines A–B (416–417), and lapidilectinol (418) from aerial part of K. lapidilecta.81,115 Three novel indole alkaloids, grandilodines A–C (411–413) were extracted from the EtOH extract of K. grandifolia stem bark or leaves with the yield ranging from 0.07 to 3.18%, and their chemical structures were proved by NMR, MS, and X-ray spectral data.72 The eight remainders, including lundurines A–B (419–422), tenuisine A–C (423–425), and tenuiphylline (426), were novel lundurines presented in the K. tenuis leaf.71,116,117 In which compounds 423–425 were unprecedented dimers, while compound 426 is unique due to the incorporation between aspidofractinine and lundurine units. As of a consequence, Kopsia lundurines, especially compounds 423–426, could be seen as significant chemotaxonomic agents.

2.8. Aspidospermas, catharinensines, leuconoxines, pericines, alstonines, and quebrachamines

Alkaloid type aspidospermas were named following the name of the genus Aspidospermas (family Apocynaceae). With regard to genus Kopsia, five known isolates 427–431 were summarized in Table 1 and Fig. 8. It turns out that buchtienine (427) was presented in either the leaf or stem of K. griffithii.15,17 The MeOH extract of K. hainanensis twig and leaf consisted of two aspidospermas, corynantheol (428) and dihydrocorynantheol (430).9 Only K. officinalis stem was found to contain 19,20-dihydroisositsirikine (429), while its congener 16(R)-19,20-E-isositsirikine (431) has been observed in the leaf of both K. griffithii and K. pauciflora.15,17,22 Therefore, alkaloidal aspidospermas are usefully chemotaxonomic agents to confirm the close relationship between the genus Kopsia and other genera in the family Apocynaceae.
image file: d2ra01791a-f8.tif
Fig. 8 Aspidospermas, catharinensines, leuconoxines, pericines, alstonines and quebrachamines from genus Kopsia.

Catharinensines, which belong to the group of oxindole alkaloids, can be found in several higher plants, such as Peschiera catharinensis.126 In Kopsia plants, five catharinensines 432–436 were detected (Table 1 and Fig. 8). Phytochemical research conducted by Gan and partners revealed that the use of mobile phase CHCl3–MeOH is appropriate to isolate alkaloidal catharinensines.22 By this approach, three new compounds, kopsirensines A–C (433–435), together with known analog catharinensine (432), have been successfully purified from the acidic EtOH extract of K. pauciflora leaves.22 New catharinensine kopsiyunnanine B (436) was first collected as a light yellow solid from the alcoholic extract of K. officinalis aerial part, and then was detected in the K. arborea aerial part.96,97

Phytochemical studies on Kopsia plants have also led to the isolation of alkaloid leuconoxines 437–442, and their structures were compiled in Fig. 8. Leuconoxine (441) was described as a major component since it occurred in K. arborea stem bark, K. griffithii leaf and stem bark, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark, K. teoi stem bark.15,17,19,22,23,43 Arboloscine (437) was one of the new compounds in K. arborea stem bark, while melodinine E (442) was a known metabolite extracted from its twigs.10,21,118 New compound arboloscine A (438) isolated from K. pauciflora leaf has a similarity in structural feature with compound 437, but the methyl group of 437 was replaced by the ethyl group in 438.22 In the genus Kopsia, leuconodine D (439) was only detected in K. officinalis stems, whereas leuconodine F (440) was characteristic of K. griffithii leaves and K. pauciflora leaves.22,43,75

To find bioactive molecules from medicinal plants, four alkaloids type pericines, including two new compounds pericidine (443) and pericine N-oxide (445) and two known analogs pericine (444) and valparicine (446) were isolated (Table 1 and Fig. 8). All of these isolates originated from K. arborea stem bark.10,118,119

To the best of our knowledge, only three compounds 447–449 were classified as alkaloid alstonines (Table 1 and Fig. 8). Oxayohimban-16-carboxy acid (447) derived from K. officinalis stem has never been isolated from the genus Kopsia before.75 The major component (−)-tetrahydroalstonine (448) appeared in K. arborea stem bark, K. dasyrachis stem, K. griffithii leaf, K. officinalis root, twig and leaf, K. larutensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark; K. teoi stem bark.10,15,17–19,22,23,25,32,42,43,66 Compound 449, a pseudoindoxyl derivative of compound 448, was identified to be a new constituent from the acidic EtOH extract of K. pauciflora leaves.22

In the same manner, there are only three quebrachamines from the genus Kopsia till now (Table 1 and Fig. 8). (−)-Quebrachamine (452) is now abundant in nature and can be found in K. arborea aerial parts, K. hainanensis twigs and leaves, K. officinalis roots, and K. pauciflora leaves.9,22,69,114 However, kopsiyunnanines D and H (450–451) from K. arborea aerial part were confirmed to be two new analogs.90,114

2.9. Others indole alkaloids and non-alkaloids

Phytochemical studies on Kopsia plants also recorded the appearance of other alkaloidal types (Table 1 and Fig. 9). Chromatographic procedure on the acidic MeOH extract of K. arborea bark has resulted in the isolation of three new metabolites, arbophyllinines A–B (453–454) and arbophyllidine (463).59 Arboflorine (455) from K. arborea stem bark was a known alkaloid type arboflorine, but its new analog kopsiyunnanine E (456) was detected in the aerial part of K. arborea and K. officinalis.10,96,99,121 Besides the main constituents, the EtOH extract of K. pauciflora leaves has composed of a new component, andransinine A (458), along with a known one andransinine (457).22 New corynantheines arboricine (459) and arboricine (460) were found in both the leaves and stem of K. arborea.10,120 The new carboline harmane (461) was presented in both leaves and stem of K. griffithii, but the new congener harmicine (462) was only detected in its leaves.15,17 To find bioactive compounds from plants, mersicarpine (464) was first isolated from K. arborea stem bark.10 It was then further found in K. pauciflora leaves and K. singapurensis stem bark.22,23 Two final alkaloids, a new alkaloid type, azepane-fused tetrahydro-β-carboline kopsiyunnanine K (465) and a known alkaloid type andranginine (466), were constituents of K. arborea aerial part.102
image file: d2ra01791a-f9.tif
Fig. 9 Others type indole alkaloids from genus Kopsia.

To date, there have not been many results on the separation of non-alkaloidal constituents from the plants of the genus Kopsia. A phytochemical report from Shan and partner (2017) identified that the n-hexane extract of K. singapurensis dried leaf and bark has accompanied with the existence of five triterpenoids β-amyrin (467), β-amyrin acetate (468), β-amyrone (469), lupeol (470), lupeol acetate (471), and one sterol stigmasterol (472) (Table 1 and Fig. 10).122 This is the first time to observe these compounds in the genus Kopsia.


image file: d2ra01791a-f10.tif
Fig. 10 Triterpenoids and sterol from genus Kopsia.

Taken together, despite the fact that there have been preliminary chemotaxonomic and synthetic reviews.127,128 This is the first time that we provide fully information on phytochemical separation, a detailed list of almost isolated compounds, chemical classification, botanical resource, and the great value of Kopisa monoterpene alkaloids in botanical and chemical relationship.

3. Pharmacological activities

Cytotoxic, antimicrobial, anti-inflammatory, anti-diabetic, cardiovascular, vasorelaxant, and other positive properties have been studied utilizing Kopsia secondary metabolites and extracts in pharmacological research. In Table 2, a summary of prior pharmacological appraisals on Kopsia plant materials is presented in detail.
Table 2 Pharmacological activities of isolated compounds and plant extracts from the genus Kopsia
Compounds Models Effect Positive control Effect References
Anti-cancer activity
39 In vitro CD50 > 60 μg mL−1/NIH/3T3 and HeLa cells Vincristine CD50 > 60 μg mL−1/NIH/3T3 cells 49
CD50 = 6.9 μg mL−1/HL-60 cells CD50 = 1.8 μg mL−1/HL-60 cells
CD50 = 0.4 μg mL−1/HeLa cells
40 In vitro CD50 > 60 μg mL−1/NIH/3T3, HL-60 and HeLa cells Vincristine CD50 > 60 μg mL−1/NIH/3T3 cells 49
CD50 = 1.8 μg mL−1/HL-60 cells
CD50 = 0.4 μg mL−1/HeLa cells
43 In vitro IC50 = 33.7 μM/HS-1 cells Adiamycin IC50 = 17.8 μM/HS-1 cells 52
IC50 = 28.4 μM/HS-4 cells IC50 = 24.7 μM/HS-4 cells
IC50 = 32.4 μM/SCL-1 cells IC50 = 21.8 μM/SCL-1 cells
IC50 = 29.7 μM/A-431 cells IC50 = 33.7 μM/A-431 cells
IC50 = 30.9 μM/BGC-823 cells IC50 = 28.4 μM/BGC-823 cells
IC50 = 27.1 μM/MCF-7 cells IC50 = 37.6 μM/MCF-7 cells
IC50 = 31.2 μM/W-480 cells IC50 = 14.1 μM/W-480 cells
44 In vitro IC50 = 34.9 μM/HS-1 cells Adiamycin IC50 = 17.8 μM/HS-1 cells 52
IC50 = 29.9 μM/HS-4 cells IC50 = 24.7 μM/HS-4 cells
IC50 = 33.1 μM/SCL-1 cells IC50 = 21.8 μM/SCL-1 cells
IC50 = 30.1 μM/A-431 cells IC50 = 33.7 μM/A-431 cells
IC50 = 35.5 μM/BGC-823 cells IC50 = 28.4 μM/BGC-823 cells
IC50 = 31.2 μM/MCF-7 cells IC50 = 37.6 μM/MCF-7 cells
IC50 = 32.6 μM/W-480 cells IC50 = 14.1 μM/W-480 cells
45 In vitro IC50 = 12.4 μM/HS-1 cells Adiamycin IC50 = 17.8 μM/HS-1 cells 52
IC50 = 12.3 μM/HS-4 and BGC-823 cells IC50 = 24.7 μM/HS-4 cells
IC50 = 12.9 μM/SCL-1 cells IC50 = 21.8 μM/SCL-1 cells
IC50 = 11.8 μM/A-431 cells IC50 = 33.7 μM/A-431 cells
IC50 = 12.6 μM/MCF-7 cells IC50 = 28.4 μM/BGC-823 cells
IC50 = 13.8 μM/W-480 cells IC50 = 37.6 μM/MCF-7 cells
  IC50 = 14.1 μM/W-480 cells
46 In vitro IC50 = 11.6 μM/HS-1 cells Adiamycin IC50 = 17.8 μM/HS-1 cells 52
IC50 = 11.4 μM/HS-4 cells IC50 = 24.7 μM/HS-4 cells
IC50 = 12.1 μM/SCL-1 cells IC50 = 21.8 μM/SCL-1 cells
IC50 = 10.3 μM/A-431 cells IC50 = 33.7 μM/A-431 cells
IC50 = 11.7 μM/BGC-823 cells IC50 = 28.4 μM/BGC-823 cells
IC50 = 10.4 μM/MCF7 cells IC50 = 37.6 μM/MCF-7 cells
IC50 = 12.5 μM/W-480 cells IC50 = 14.1 μM/W-480 cells
47 In vitro IC50 = 7.3 μM/HS-1 cells Adiamycin IC50 = 17.8 μM/HS-1 cells 52
IC50 = 8.6 μM/HS-4 and MCF-7 cells IC50 = 24.7 μM/HS-4 cells
IC50 = 8.2 μM/SCL-1 cells IC50 = 21.8 μM/SCL-1 cells
IC50 = 9.5 μM/A431 cells IC50 = 33.7 μM/A-431 cells
IC50 = 8.9 μM/BGC-823 cells IC50 = 28.4 μM/BGC-823 cells
IC50 = 9.2 μM/W-480 cells IC50 = 37.6 μM/MCF-7 cells
IC50 = 14.1 μM/W-480 cells
48 In vitro IC50 = 11.3 μM/A-549 cells Doxorubicin IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells 53
IC50 = 9.4 μM/BGC-823 cells IC50 = 0.01 μM/BGC-823 cells
IC50 = 10.1 μM/HepG-2 cells IC50 = 0.03 μM/HL-60 cells
IC50 = 11.1 μM/HL-60 cells IC50 = 0.04 μM/SMMC-7721 cells
IC50 = 10.4 μM/MCF-7 cells  
IC50 = 9.7 μM/SMMC-7721 cells
IC50 = 11.7 μM/W-480 cells
49 In vitro IC50 = 12.7 μM/A-549 cells Doxorubicin IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells 53
IC50 = 12.2 μM/BGC-823 cells IC50 = 0.01 μM/BGC-823 cells
IC50 = 12.8 μM/HepG-2 cells IC50 = 0.03 μM/HL-60 cells
IC50 = 13.8 μM/HL-60 cells IC50 = 0.04 μM/SMMC-7721 cells
IC50 = 14.3 μM/MCF-7 and SMMC-7721 cells  
IC50 = 15.9 μM/W-480 cells  
50 In vitro IC50 = 31.9 μM/A-549 cells Doxorubicin IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells 53
IC50 = 31.2 μM/BGC-823 cells IC50 = 0.01 μM/BGC-823 cells
IC50 = 30.7 μM/HepG-2 cells IC50 = 0.03 μM/HL-60 cells
IC50 = 32.2 μM/HL-60 cells IC50 = 0.04 μM/SMMC-7721 cells
IC50 = 28.1 μM/MCF-7 cells  
IC50 = 29.9 μM/SMMC-7721 cells  
IC50 = 27.6 μM/W-480 cells  
51 In vitro IC50 = 29.7 μM/A-549 cells Doxorubicin IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells 53
IC50 = 29.6 μM/BGC-823 cells IC50 = 0.01 μM/BGC-823 cells
IC50 = 29.4 μM/HepG-2 and HL-60 cells IC50 = 0.03 μM/HL-60 cells
IC50 = 27.1 μM/MCF-7 cells IC50 = 0.04 μM/SMMC-7721 cells
IC50 = 30.1 μM/SMMC-7721 cells  
IC50 = 24.9 μM/W-480 cells  
52 In vitro IC50 = 76.3 μM/A-549 cells Doxorubicin IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells 53
IC50 = 68.7 μM/BGC-823 cells IC50 = 0.01 μM/BGC-823 cells
IC50 = 66.8 μM/HepG-2 cells IC50 = 0.03 μM/HL-60 cells
IC50 = 72.3 μM/HL-60 cells IC50 = 0.04 μM/SMMC-7721 cells
IC50 = 76.2 μM/MCF-7 cells  
IC50 = 70.8 μM/SMMC-7721 cells  
IC50 = 69.4 μM/W-480 cells  
53 In vitro IC50 = 80.2 μM/A-549 cells Doxorubicin IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells 53
IC50 = 78.8 μM/BGC-823 cells IC50 = 0.01 μM/BGC-823 cells
IC50 = 79.4 μM/HepG-2 cells IC50 = 0.03 μM/HL-60 cells
IC50 = 80.3 μM/HL-60 cells IC50 = 0.04 μM/SMMC-7721 cells
IC50 = 80.5 μM/MCF-7 cells  
IC50 = 81.6 μM/SMMC-7721 cells  
IC50 = 81.8 μM/W-480 cells  
54 In vitro IC50 = 15.8 μM/BGC-823 cells Doxorubicin IC50 = 0.02 μM/BGC-823 cells 54
IC50 = 16.8 μM/HepG-2 cells IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
IC50 = 16.5 μM/MCF-7 cells IC50 = 0.06 μM/MCF-7 cells
IC50 = 18.7 μM/SGC-7901 cells IC50 = 0.05 μM/SGC-7901 cells
IC50 = 19.7 μM/SK-MEL-2 cells IC50 = 0.03 μM/SK-MEL-2 cells
IC50 = 17.6 μM/SK-OV-3 cells  
55 In vitro IC50 = 13.8 μM/BGC-823 cells Doxorubicin IC50 = 0.02 μM/BGC-823 cells 54
IC50 = 12.4 μM/HepG-2 cells IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
IC50 = 14.8 μM/MCF-7 cells IC50 = 0.06 μM/MCF-7 cells
IC50 = 13.9 μM/SGC-7901 and SK-OV-3 cells IC50 = 0.05 μM/SGC-7901 cells
IC50 = 12.6 μM/SK-MEL-2 cells IC50 = 0.03 μM/SK-MEL-2 cells
56 In vitro IC50 = 7.3 μM/BGC-823 cells Doxorubicin IC50 = 0.02 μM/BGC-823 cells 54
IC50 = 8.6 μM/HepG-2 cells IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
IC50 = 8.2 μM/MCF-7 cells IC50 = 0.06 μM/MCF-7 cells
IC50 = 9.5 μM/SGC-7901 cells IC50 = 0.05 μM/SGC-7901 cells
IC50 = 8.9 μM/SK-MEL-2 cells IC50 = 0.03 μM/SK-MEL-2 cells
IC50 = 8.6 μM/SK-OV-3 cells  
57 In vitro IC50 = 9.5 μM/BGC-823 cells Doxorubicin IC50 = 0.02 μM/BGC-823 cells 54
IC50 = 10.6 μM/HepG-2 cells IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
IC50 = 9.3 μM/MCF-7 cells IC50 = 0.06 μM/MCF-7 cells
IC50 = 10.4 μM/SGC-7901 cells IC50 = 0.05 μM/SGC-7901 cells
IC50 = 9.2 μM/SK-MEL-2 cells IC50 = 0.03 μM/SK-MEL-2 cells
IC50 = 10.3 μM/SK-OV-3 cells  
58 In vitro IC50 = 33.1 μM/BGC-823 cells Doxorubicin IC50 = 0.02 μM/BGC-823 cells 54
IC50 = 32.4 μM/HepG-2 cells IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
IC50 = 29.7 μM/MCF-7 cells IC50 = 0.06 μM/MCF-7 cells
IC50 = 30.9 μM/SGC-7901 cells IC50 = 0.05 μM/SGC-7901 cells
IC50 = 27.1 μM/SK-MEL-2 cells IC50 = 0.03 μM/SK-MEL-2 cells
IC50 = 30.1 μM/SK-OV-3 cells  
59 In vitro IC50 = 12.9 μM/95-D cells Doxorubicin IC50 = 24.7 μM/95-D cells 55
IC50 = 12.4 μM/A-549 cells IC50 = 21.8 μM/A-549 cells
IC50 = 13.8 μM/ATCC cells IC50 = 33.7 μM/ATCC cells
IC50 = 14.8 μM/H-446 cells IC50 = 22.3 μM/H-446 cells
IC50 = 13.3 μM/H-460 cells IC50 = 14.1 μM/H-460 cells
IC50 = 12.6 μM/H-292 cells IC50 = 13.7 μM/H-292 cells
IC50 = 13.9 μM/SPCA-1 cells IC50 = 14.1 μM/SPCA-1 cells
60 In vitro IC50 = 46.8 μM/95-D cells Doxorubicin IC50 = 24.7 μM/95-D cells 55
IC50 = 47.1 μM/ATCC cells IC50 = 33.7 μM/ATCC cells
IC50 = 46.6 μM/H-446 cells IC50 = 22.3 μM/H-446 cells
IC50 = 45.9 μM/H-292 cells IC50 = 13.7 μM/H-292 cells
61 In vitro IC50 = 9.5 μM/95-D cells Doxorubicin IC50 = 24.7 μM/95-D cells 55
IC50 = 8.6 μM/A-549 cells IC50 = 21.8 μM/A-549 cells
IC50 = 9.3 μM/ATCC and H-292 cells IC50 = 33.7 μM/ATCC cells
IC50 = 9.4 μM/H-446 cells IC50 = 22.3 μM/H-446 cells
IC50 = 9.2 μM/H-460 cells IC50 = 14.1 μM/H-460 cells
IC50 = 9.7 μM/SPCA-1 cells IC50 = 13.7 μM/H-292 cells
  IC50 = 14.1 μM/SPCA-1 cells
73 In vitro CD50 = 20.7 μg mL−1/NIH/3T3 cells Vincristine CD50 > 60 μg mL−1/NIH/3T3 cells 49
CD50 = 0.9 μg mL−1/HL-60 cells CD50 = 1.8 μg mL−1/HL-60 cells
CD50 = 36.5 μg mL−1/HeLa cells CD50 = 0.4 μg mL−1/HeLa cells
74 In vitro To suppress the bound of [3H]azidopine to P-glycoprotein     61
76 In vitro IC50 = 67.3 μM/HS-4 cells Adiamycin IC50 = 24.7 μM/HS-4 cells 52
IC50 = 74.2 μM/A-431 cells IC50 = 33.7 μM/A-431 cells
IC50 = 66.2 μM/W-480 cells IC50 = 14.1 μM/W-480 cells
88 In vitro IC50 = 38.7 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 43
93 In vitro IC50 = 19.5 μg mL−1/KB cells Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 32
IC50 = 18.0 μg mL−1/KB (VJ300) cells
IC50 = 3.80 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
102 In vitro IC50 = 15.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 23
103 In vitro IC50 = 3.9 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 23
104 In vitro IC50 = 13.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 23
105 In vitro IC50 = 18.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 23
106 In vitro IC50 = 9.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 23
107 In vitro IC50 = 18.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 23
214 In vitro IC50 = 29.7 μM/BGC-823 cells Doxorubicin IC50 = 29.7 μM/BGC-823 cells 85
IC50 = 37.6 μM/HepG-2 cells IC50 = 37.6 μM/HepG-2 cells
IC50 = 35.8 μM/MCF-7 cells IC50 = 35.8 μM/MCF-7 cells
IC50 = 36.8 μM/SGC-7901 cells IC50 = 36.8 μM/SGC-7901 cells
IC50 = 36.5 μM/SK-MEL-2 cells IC50 = 36.5 μM/SK-MEL-2 cells
215 In vitro IC50 = 32.1 μM/BGC-823 cells Doxorubicin IC50 = 29.7 μM/BGC-823 cells 85
IC50 = 29.8 μM/HepG-2 cells IC50 = 37.6 μM/HepG-2 cells
IC50 = 31.9 μM/MCF-7 cells IC50 = 35.8 μM/MCF-7 cells
IC50 = 27.9 μM/SGC-7901 cells IC50 = 36.8 μM/SGC-7901 cells
IC50 = 33.3 μM/SK-MEL-2 cells IC50 = 36.5 μM/SK-MEL-2 cells
237 In vitro IC50 = 8.6 μM/BGC-823 cells Doxorubicin IC50 = 29.7 μM/BGC-823 cells 85
IC50 = 7.2 μM/HepG-2 cells IC50 = 37.6 μM/HepG-2 cells
IC50 = 8.3 μM/MCF-7 cells IC50 = 35.8 μM/MCF-7 cells
IC50 = 8.2 μM/SGC-7901 cells IC50 = 36.8 μM/SGC-7901 cells
IC50 = 8.9 μM/SK-MEL-2 cells IC50 = 36.5 μM/SK-MEL-2 cells
282 In vitro IC50 = 9.7 μg mL−1/PC-3 cells Cisplatin IC50 = 1.5 μg mL−1/PC-3 cells 19
IC50 = 15.9 μg mL−1/HCT-116 cells IC50 = 3.2 μg mL−1/HCT-116 cells
IC50 = 14.1 μg mL−1/MCF-7 cells IC50 = 4.2 μg mL−1/MCF-7 cells
IC50 > 25 μg mL−1/A-549 and KB (VJ300) cells IC50 = 4.3 μg mL−1/A-549 cells
IC50 = 8.6 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Verapamil IC50 = 4.7 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
289 In vitro IC50 = 7.1 μg mL−1/PC-3 cells Cisplatin IC50 = 1.5 μg mL−1/PC-3 cells 19
IC50 = 7.6 μg mL−1/HCT-116 cells IC50 = 3.2 μg mL−1/HCT-116 cells
IC50 = 9.7 μg mL−1/MCF-7 cells IC50 = 4.2 μg mL−1/MCF-7 cells
IC50 = 20.4 μg mL−1/A-549 cells IC50 = 4.3 μg mL−1/A-549 cells
IC50 = 23 μg mL−1/KB (VJ300) cells  
IC50 = 4.80 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Verapamil IC50 = 4.7 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
302 In vitro CD50 > 60 μg mL−1/NIH/3T3 cells Vincristine CD50 > 60 μg mL−1/NIH/3T3 cells 49
CD50 = 30.2 μg mL−1/HL-60 cells CD50 = 1.8 μg mL−1/HL-60 cells
CD50 = 2.8 μg mL−1/HeLa cells CD50 = 0.4 μg mL−1/HeLa cells
327 In vitro CD50 = 6.4 μg mL−1/NIH/3T3 cells Vincristine CD50 > 60 μg mL−1/NIH/3T3 cells 49
CD50 > 60 μg mL−1/HL-60 cells CD50 = 1.8 μg mL−1/HL-60 cells
CD50 = 7.5 μg mL−1/HeLa cells CD50 = 0.4 μg mL−1/HeLa cells
333 In vitro IC50 = 1.3 μg mL−1/HT-29 cells Cisplatin IC50 = 8.8 μg mL−1/HT-29 cells 8
IC50 = 4.9 μg mL−1/MCF-7 cells IC50 = 6.6 μg mL−1/MCF-7 cells
IC50 = 4.7 μg mL−1/PC-3 cells IC50 = 4.2 μg mL−1/PC-3 cells
IC50 = 7.0 μg mL−1/MDA-MB -231 cells IC50 = 2.1 μg mL−1/MDA-MB -231 cells
IC50 = 7.3 μg mL−1/HCT-116 cells IC50 = 4.6 μg mL−1/HCT-116 cells
IC50 = 9.6 μg mL−1/A-549 cells IC50 = 5.4 μg mL−1/A-549 cells
IC50 = 3.0 μg mL−1/KB (VJ300) cells Vincristine IC50 = 0.8 μg mL−1/KB (VJ300) cells
366 In vitro IC50 = 3.70 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 103
367 In vitro IC50 = 7.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 103
373 In vitro IC50 = 4.1 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 103
374 In vitro IC50 = 3.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 103
375 In vitro IC50 = 11.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 103
402 In vitro IC50 = 5.38 μM/A-549 cells Docetaxel IC50 = 4.95 × 10−4 μM/A-549 cells 114
IC50 = 4.67 μM/HT-29 cells IC50 = 3.34 × 10−4 μM/HT-29 cells
403 In vitro IC50 = 7.44 μM/A-549 cells Docetaxel IC50 = 4.95 × 10−4 μM/A-549 cells 114
IC50 = 6.39 μM/HT-29 cells IC50 = 3.34 × 10−4 μM/HT-29 cells
404 In vitro IC50 = 8.21 μM/A-549 cells Docetaxel IC50 = 4.95 × 10−4 μM/A-549 cells 114
IC50 = 8.89 μM/HT-29 cells IC50 = 3.34 × 10−4 μM/HT-29 cells
407 In vitro IC50 = 0.24 μg mL−1/KB cells Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 32
IC50 = 0.25 μg mL−1/KB (VJ300) cells
IC50 = 0.30 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
408 In vitro CD50 = 20.8 μg mL−1/NIH/3T3 cells Vincristine CD50 > 60 μg mL−1/NIH/3T3 cells 49
CD50 > 60 μg mL−1/HL-60 cells CD50 = 1.8 μg mL−1/HL-60 cells
CD50 = 2.9 μg mL−1/HeLa cells CD50 = 0.4 μg mL−1/HeLa cells
IC50 = 0.19 μg mL−1/KB cells Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 32
IC50 = 0.25 μg mL−1/KB (VJ300) cells
IC50 = 0.34 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
409 In vitro IC50 = 0.35 μM/A-549 and HT-29 cells Docetaxel IC50 = 4.95 × 10−4 μM/A-549 cells 114
IC50 = 1.25 μg mL−1/KB cells IC50 = 3.34 × 10−4 μM/HT-29 cells
IC50 = 2.50 μg mL−1/KB (VJ300) cells Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 32
IC50 = 1.85 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
411 In vitro IC50 = 4.35 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 72
413 In vitro IC50 = 4.11 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 72
417 In vitro IC50 = 0.39 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 72
434 In vitro IC50 = 21.8 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 22
437 In vitro IC50 = 15.0 μg mL−1/KB cells Vincadifformine IC50 = 10.2 μg mL−1/KB cells 10
IC50 = 11.0 μg mL−1/KB (VJ300) cells IC50 = 6.3 μg mL−1/KB (VJ300) cells
IC50 = 3.8 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine IC50 = 4.5 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
438 In vitro IC50 = 6.4 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine Vincristine IC50 = 1.0 μg mL−1/KB (VJ300) 22
446 In vitro IC50 = 0.25 μg mL−1/Jurkat cells Vincadifformine IC50 = 21.8 μg mL−1/Jurkat cells 10
IC50 = 3.6 μg mL−1/KB cells IC50 = 10.2 μg mL−1/KB cells
IC50 = 0.75 μg mL−1/KB (VJ300) cells IC50 = 6.3 μg mL−1/KB (VJ300) cells
IC50 = 0.46 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine IC50 = 4.5 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
450 and 452 In vitro IC50 > 30 μM/A-549 cells Docetaxel IC50 = 4.95 × 10−4 μM/A-549 cells 114
IC50 = 30 μM/HT-29 cells IC50 = 3.34 × 10−4 μM/HT-29 cells
463 In vitro IC50 = 6.2 μM/HT-29 cells     59
467 In vitro IC50 = 15.5 μg mL−1/MCF-7 cells     122
468 In vitro IC50 = 22.5 μg mL−1/MCF-7 cells     122
469 In vitro IC50 = 21.5 μg mL−1/MCF-7 cells     122
470 In vitro IC50 = 17 μg mL−1/MCF-7 cells     122
471 In vitro IC50 = 26 μg mL−1/MCF-7 cells     122
472 In vitro IC50 = 14.5 μg mL−1/MCF-7 cells     122
[thin space (1/6-em)]
Anti-microbial activity
14 In vitro MIC = 31.3 μg mL−1/E. coli, E. carotovra, B. subtilis, B. cereus, and S. aureus Ampicillin MIC = 100 μg mL−1/E. coli and E. carotovra 7
MIC = 15.5 μg mL−1/E. carotovra MIC = 12.5 μg mL−1/B. subtilis
  MIC = 25.0 μg mL−1/B. cereus and S. aureus
EC50 = 33.3 μg mL−1/R. solani Mildothane EC50 = 17.0 μg mL−1/R. solani
EC50 = 29.2 μg mL−1/P. italicum EC50 = 7.8 μg mL−1/P. italicum
EC50 = 16.3 μg mL−1/F. oxysporum f. sp. Cubense EC50 = 57.0 μg mL−1/F. oxysporum f. sp. Cubense
EC50 = 31.8 μg mL−1/F. oxysporum f. sp. Niveum EC50 = 101.0 μg mL−1/F. oxysporum f. sp. Niveum
43 In vitro IZ = 11 mm/K. pneumoniae Sanguinarine IZ = 25 mm/S. mutans and S. viridans 52
IZ = 10 mm/E. coli, S. aureus and S. viridans Netilmicin IZ = 21 mm/S. aureus
IZ = 9 mm/C. glabrata, E. cloacae and S. mutans IZ = 8 mm/S. epidermidis and K. pneumoniae
IZ = 8 mm/S. epidermidis and S. dysenteriae IZ = 24 mm/E. coli
IZ = 7 mm/C. albicans, C. tropicalis and P. aeruginosa IZ = 22 mm/E. cloacae
  IZ = 23 mm/P. aeruginosa and S. dysenteriae
44 In vitro IZ = 12 mm/P. aeruginosa and S. mutans Sanguinarine IZ = 25 mm/S. mutans and S. viridans 52
IZ = 11 mm/E. coli Netilmicin IZ = 21 mm/S. aureus
IZ = 10 mm/C. glabrata IZ = 8 mm/S. epidermidis and K. pneumoniae
IZ = 9 mm/E. cloacae, S. aureus and S. dysenteriae IZ = 24 mm/E. coli
IZ = 8 mm/C. albicans, K. pneumoniae and S. epidermidis IZ = 22 mm/E. cloacae
IZ = 7 mm/C. tropicalis and S. viridans IZ = 23 mm/P. aeruginosa and S. dysenteriae
45 In vitro IZ = 18 mm and MIC = 0.77 mM/K. pneumoniae Sanguinarine IZ = 25 mm/S. mutans and S. viridans 52
IZ = 18 mm and MIC = 0.87 mM/S. viridans Netilmicin IZ = 21 mm/S. aureus
IZ = 17 mm and MIC = 0.89 mM/E. coli IZ = 8 mm/S. epidermidis and K. pneumoniae
IZ = 18 mm and MIC = 0.97 mM/S. aureus and S. epidermidis IZ = 24 mm/E. coli
IZ = 18 mm and MIC = 0.97 mM/E. cloacae IZ = 22 mm/E. cloacae
IZ = 19 mm and MIC = 1.01 mM/P. aeruginosa IZ = 23 mm/P. aeruginosa and S. dysenteriae
IZ = 18 mm and MIC = 1.13 mM/S. mutans  
IZ = 19 mm and MIC = 1.18 mM/C. tropicalis  
IZ = 18 mm and MIC = 2.68 mM/S. dysenteriae  
IZ = 17 mm and MIC = 2.87 mM/C. albicans  
IZ = 17 mm and MIC = 3.09 mM/C. glabrata  
46 In vitro IZ = 20 mm and MIC = 0.72 mM/E. coli Sanguinarine IZ = 25 mm/S. mutans and S. viridans 52
IZ = 20 mm and MIC = 0.82 mM/S. mutans
IZ = 20 mm and MIC = 0.91 mM/S. epidermidis
IZ = 20 mm and MIC = 1.03 mM/S. dysenteriae
IZ = 20 mm and MIC = 1.11 mM/S. viridans
IZ = 20 mm and MIC = 1.18 mM/P. aeruginosa Netilmicin IZ = 21 mm/S. aureus
IZ = 19 mm and MIC = 1.20 mM/E. cloacae IZ = 8 mm/S. epidermidis and K. pneumoniae
IZ = 20 mm and MIC = 1.23 mM/C. tropicalis and S. aureus IZ = 24 mm/E. coli
IZ = 17 mm and MIC = 1.32 mM/C. glabrata IZ = 22 mm/E. cloacae
IZ = 21 mm and MIC = 1.37 mM/K. pneumoniae IZ = 23 mm/P. aeruginosa and S. dysenteriae
IZ = 17 mm and MIC = 2.87 mM/C. albicans  
47 In vitro IZ = 24 mm and MIC = 0.15 mM/E. coli Sanguinarine IZ = 25 mm/S. mutans and S. viridans 52
IZ = 24 mm and MIC = 0.20 mM/S. epidermidis
IZ = 23 mm and MIC = 0.22 mM/C. glabrata
IZ = 23 mm and MIC = 0.30 mM/C. tropicalis
IZ = 24 mm and MIC = 0.30 mM/S. dysenteriae and C. albicans
IZ = 24 mm and MIC = 0.25 mM/S. aureus Netilmicin IZ = 21 mm/S. aureus
IZ = 24 mm and MIC = 0.27 mM/E. cloacae IZ = 8 mm/S. epidermidis and K. pneumoniae
IZ = 24 mm and MIC = 0.32 mM/P. aeruginosa IZ = 24 mm/E. coli
IZ = 23 mm and MIC = 0.37 mM/K. pneumoniae IZ = 22 mm/E. cloacae
IZ = 23 mm and MIC = 0.87 mM/S. viridans IZ = 23 mm/P. aeruginosa and S. dysenteriae
IZ = 24 mm and MIC = 1.14 mM/S. mutans  
48 In vitro IZ = 23 mm and MIC = 0.12 mM/K. pneumoniae Netilmicin IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae 53
IZ = 24 mm and MIC = 0.12 mM/S. dysenteriae IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
IZ = 24 mm and MIC = 0.13 mM/P. aeruginosa IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
IZ = 23 mm and MIC = 0.15 mM/E. cloacae IZ = 22 mm and MIC = 0.01 mM/E. cloacae
IZ = 23 mm and MIC = 0.16 mM/S. epidermidis IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
IZ = 24 mm and MIC = 0.18 mM/S. aureus IZ = 21 mm and MIC = 0.005 mM/S. aureus
IZ = 24 mm and MIC = 0.23 mM/E. coli IZ = 24 mm and MIC = 0.015 mM/E. coli
49 In vitro IZ = 24 mm and MIC = 0.14 mM/K. pneumoniae Netilmicin IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae 53
IZ = 23 mm and MIC = 0.16 mM/P. aeruginosa IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
IZ = 24 mm and MIC = 0.17 mM/S. aureus IZ = 21 mm and MIC = 0.005 mM/S. aureus
IZ = 22 mm and MIC = 0.18 mM/S. dysenteriae IZ = 22 mm and MIC = 0.01 mM/E. cloacae
IZ = 24 mm and MIC = 0.19 mM/E. cloacae IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
IZ = 23 mm and MIC = 0.19 mM/S. epidermidis IZ = 24 mm and MIC = 0.015 mM/E. coli
IZ = 24 mm and MIC = 0.26 mM/E. coli  
50 In vitro IZ = 18 mm and MIC = 0.94 mM/P. aeruginosa Netilmicin IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa 53
IZ = 17 mm and MIC = 1.10 mM/E. cloacae IZ = 22 mm and MIC = 0.01 mM/E. cloacae
IZ = 17 mm and MIC = 1.12 mM/K. pneumoniae and S. dysenteriae IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae
IZ = 18 mm and MIC = 1.20 mM/S. aureus IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
IZ = 19 mm and MIC = 1.23 mM/S. epidermidis IZ = 21 mm and MIC = 0.005 mM/S. aureus
IZ = 18 mm and MIC = 1.32 mM/E. coli IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
  IZ = 24 mm and MIC = 0.015 mM/E. coli
51 In vitro IZ = 17 mm and MIC = 0.92 mM/P. aeruginosa Netilmicin IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa 53
IZ = 18 mm and MIC = 1.01 mM/E. cloacae IZ = 22 mm and MIC = 0.01 mM/E. cloacae
IZ = 19 mm and MIC = 1.02 mM/S. dysenteriae IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
IZ = 18 mm and MIC = 1.09 mM/K. pneumoniae IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae
IZ = 19 mm and MIC = 1.15 mM/S. epidermidis IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
IZ = 20 mm and MIC = 1.18 mM/S. aureus IZ = 21 mm and MIC = 0.005 mM/S. aureus
IZ = 17 mm and MIC = 1.24 mM/E. coli IZ = 24 mm and MIC = 0.015 mM/E. coli
52 In vitro IZ = 17 mm and MIC = 1.19 mM/K. pneumoniae Netilmicin IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae 53
IZ = 18 mm and MIC = 1.21 mM/E. coli IZ = 24 mm and MIC = 0.015 mM/E. coli
IZ = 17 mm and MIC = 1.21 mM/P. aeruginosa IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
IZ = 17 mm and MIC = 1.31 mM/E. cloacae IZ = 22 mm and MIC = 0.01 mM/E. cloacae
IZ = 15 mm and MIC = 1.31 mM/S. dysenteriae IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
53 In vitro IZ = 16 mm and MIC = 0.99 mM/K. pneumoniae Netilmicin IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae 53
IZ = 18 mm and MIC = 1.01 mM/S. dysenteriae IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
IZ = 17 mm and MIC = 1.24 mM/P. aeruginosa IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
IZ = 15 mm and MIC = 1.31 mM/E. coli IZ = 24 mm and MIC = 0.015 mM/E. coli
IZ = 17 mm and MIC = 1.32 mM/E. cloacae IZ = 22 mm and MIC = 0.01 mM/E. cloacae
74 In vitro IZ = 9.7 mm/S. aureus Kanamycin sulfate IZ = 24.7 mm/S. aureus 12
76 In vitro IZ = 13 mm/S. aureus Kanamycin sulfate IZ = 24.7 mm/S. aureus 12
IZ = 12 mm/S. epidermidis
IZ = 9 mm/ C. albicans and C. glabrata
IZ = 8 mm/C. tropicalis, S. mutans and S. dysenteriae
IZ = 7 mm/E. coli and K. pneumoniae
85 In vitro IZ = 11.2 mm/S. aureus Kanamycin sulfate IZ = 24.7 mm/S. aureus 12
86 In vitro IZ = 9.1 mm/S. aureus Kanamycin sulfate IZ = 24.7 mm/S. aureus 12
87 In vitro IZ = 10.3 mm/S. aureus Kanamycin sulfate IZ = 24.7 mm/S. aureus 12
206 In vitro MIC = 15.5 μg mL−1/E. coli, Erwinia carotovra, Bacillus subtilis, B. cereus, and S. aureus Ampicillin MIC = 100 μg mL−1/E. coli and E. carotovra 7
MIC = 7.8 μg mL−1/E. carotovra
EC50 = 21.9 μg mL−1/R. solani Mildothane MIC = 12.5 μg mL−1/B. subtilis
EC50 = 19.4 μg mL−1/P. italicum MIC = 25.0 μg mL−1/B. cereus and S. aureus
EC50 = 15.2 μg mL−1/F. oxysporum f. sp. Cubense EC50 = 17.0 μg mL−1/R. solani
EC50 = 43.8 μg mL−1/F. oxysporum f. sp. Niveum EC50 = 7.8 μg mL−1/P. italicum
  EC50 = 57.0 μg mL−1/F. oxysporum f. sp. Cubense
  EC50 = 101.0 μg mL−1/F. oxysporum f. sp. Niveum
267 and 297 In vitro MIC = 32 μg mL−1/E. coli     21
[thin space (1/6-em)]
Anti-inflammatory activity
11 In vitro IC50 = 25.4 μM/T cell inhibition     16
170 In vitro IC50 = 21.6 μM/T cell inhibition     16
222 In vitro IC50 = 27.8 μM/T cell inhibition     16
409 In vitro IC50 = 1.0 μM/T cell inhibition     16
To arrest the G2/M phase of the T cell cycle
To decrease IL-6 and IL-17 levels in T cells
219, 225, 228, 279–280, 291, and 439 In vitro The inhibitory effects on IL-1β and TNF-α, and PGE2 were comparable with positive control dexamethasone     75
[thin space (1/6-em)]
Anti-allergic activity
90 In vitro IC10 = 3.73 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 66
126 In vitro IC10 = 7.06 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 66
257 In vitro IC10 = 5.51 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 66
448 In vitro IC10 = 11.78 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 66
The MeOH extract of K. larutensis bark In vitro IC10 = 2.17 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 66
The MeOH extract of K. arborea bark In vitro IC10 = 3.82 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 129
The MeOH extract of K. larutensis leaf In vitro IC10 = 3.01 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 66
The MeOH extract of K. arborea leaf In vitro IC10 = 2.58 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 129
The MeOH extract of K. larutensis root In vitro IC10 = 1.61 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 66
The MeOH extract of K. arborea root In vitro IC10 = 4.32 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell Ketotifen fumarate IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell 129
[thin space (1/6-em)]
Anti-diabetic activity
29 In vitro EC50 = 24.5 μM/glucose-evoked podocyte injury inhibition Astragaloside IV EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition 25
126 In vitro EC50 = 3.0 μM/glucose-evoked podocyte injury inhibition Astragaloside IV EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition 25
224 In vitro EC50 = 10.2 μM/glucose-evoked podocyte injury inhibition Astragaloside IV EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition 25
264 In vitro EC50 = 12.0 μM/glucose-evoked podocyte injury inhibition Astragaloside IV EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition 25
405 In vitro EC50 = 3.80 μM/glucose-evoked podocyte injury inhibition Astragaloside IV EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition 25
379 and 384–386 In vitro IC50 > 50 μM/α-glucosidase inhibition     109
[thin space (1/6-em)]
AChE inhibitory activity
39 In vitro MIR = 12.5 μg/AChE inhibition Galanthamine MIR = 0.004 μg/AChE inhibition 21
220 In vitro IC50 = 12.5 μg/AChE inhibition     6
221 In vitro IC50 = 12.5 μg/AChE inhibition     6
[thin space (1/6-em)]
Anti-manic activity
165 In vitro IC50 = 12.5 mg mL−1/anti-manic activity in Drosophila     13
[thin space (1/6-em)]
Anti-tussive activity
126 In vivo 88% Cough inhibition/citric acid activated Guinea pig cough model     65
Interaction to δ-opioid receptor
250 In vivo 76% Cough inhibition/citric acid activated Guinea pig cough model     65
[thin space (1/6-em)]
Anti-nociceptive activity
The alkaloidal extract of K. macrophylla In vivo To decrease in the number of contortion and stretching via peripheral mechanism     130
[thin space (1/6-em)]
Cardiovascular and vasorelaxant activities
112 In vivo To decrease arterial blood pressure and heart rate     131
208 In vivo 13% Relaxation occurred rat aorta ring     84
210 In vivo 24% Relaxation occurred rat aorta ring     84
211 In vivo 26% Relaxation occurred rat aorta ring     84
216 In vivo 28% Relaxation occurred rat aorta ring     84
219 In vivo 40% Relaxation occurred rat aorta ring     84
225 In vivo 41% Relaxation occurred rat aorta ring     84
227 In vivo 15% Relaxation occurred rat aorta ring     84
228 In vivo 37% Relaxation occurred rat aorta ring     84
229 In vivo 19% Relaxation occurred rat aorta ring     84
230 In vivo 19% Relaxation occurred rat aorta ring     84
239 In vivo 23% Relaxation occurred rat aorta ring     84

3.1. Cytotoxic activity

It is obvious to the view that monoterpene alkaloids are the major phytochemicals in Kopsia plants so that cytotoxic experiments using Kopsia constituents may be thought of as a big content in pharmacological development. Six alkaloidal constituents 39–40, 73, 302, 327, and 408 from K. singapurensis root were submitted to cytotoxic assay against NIH/3T3, HL-60, and HeLa cells.49 Among them, kopsifine (73) induced the lowest CD50 value of 0.9 μg mL−1 against HL-60 cells in referencing with the positive control vincristine (CD50 1.8 μg mL−1).49

Kopsiafrutine E (47) possessing hydroxyl groups at carbons C-14 and C-15 demonstrated as the most bioactive compound against HS-1, HS-4, SCL-1, A-431, BGC-823, MCF-7, and W-480 with the IC50 values of 7.3–9.5 μM.52 Meanwhile, its congeners kopsiafrutines C–D (45–46) containing a hydroxyl group at carbon C-15 have shown to associate with the respective IC50 values of 10.3–12.5 and 11.8–13.8 μM, but kopsiafrutines A–B (43–44) and kopsifoline A (76) did not inhibit cancer cell growth (IC50 > 20 μM).52 In the same way, the following new aspidofractinines kopsiahainanins A–B (48–49) with a lactone bridge have induced the respective IC50 values of 9.4–11.7 and 12.2–15.9 μM against A-549, BGC-823, HepG-2, HL-60, MCF-7, SMMC-7721, and W-480 cells.53 However, four new analogous kopsiahainanins C–F (50–53) accompanied by the IC50 values of >20 μM.53

From Table 2, new aspidofractines kopsiahainins A–E (54–58) were also further examined by cytotoxic test towards BGC-823, HepG-2, MCF-7, SGC-7901, SK-MEL-2, and SK-OV-3 cancer cells. It evidenced that compounds 56–57 demonstrated strong activity with IC50 values of ≤10 μM.54 Similarly, in the N(4)-oxide group, new alkaloid 237 possessed the IC50 values from 7.2 to 8.9 μM to inhibit BGC-823, HepG-2, MCF-7, SGC-7901, and SK-MEL-2 cells, but new metabolites 214–215 was inactive (IC50 > 20 μM).85

The new metabolite kopsiaofficines C (61) showed the IC50 values of <10 μM towards cancer cell lines 95-D, A-549, ATCC, H-446, H-460, H-292, and SPCA-1, and was better than its analogs 59 (10 < IC50 ≤ 20 μM) and 60 (IC50 > 20 μM).55 The bulk dimeric molecule arbolodinine B (333) successfully controlled the growth of HT-29, MCF-7, PC-3, KB (VJ300), MDA-MB-231, HCT-116, and A-549 with the IC50 values ranging from 1.3 to 9.6 μg mL−1, while arbolodinines A and C (1 and 334) failed to do so.8

Rhazinilam (409) itself displayed the potential application in cancer treatments because its strong inhibitory capacity to A-549 and HT-29 cells (IC50 0.35 μM), kopsiyunnanines A–C (402–404) indicated moderate activities (IC50 4.67–8.89 μM), but both kopsiyunnanine D (450) and (−)-quebrachamine (452) were inactive (>30 μM).114 Novel alkaloidal arbophyllidine (463) suppressed HT-29 cell growth with the IC50 value of 6.2 μM, but the novel metabolite arbophyllinine A (453) failed to inhibit.59 Six non-alkaloidal constituents 467–472 were also subjected to cytotoxic assay, in which their IC50 values ranged from 14.5 to 22.5 μg mL−1.122

Vincristine, a renowned chemotherapy medication, is usually used in combining with other drugs to treat many types of cancers.132 In this scenario, experiments using a combination of Kopsia alkaloids and vincristine for anticancer treatments also bring out significant results. In VJ300 cells, kopsiflorine 74 (10 μg mL−1) showed reversal of multiple drug resistance (MRD) by suppressing the bound of [3H]azidopine to P-glycoprotein.61 Alkaloidal compounds 88, 102–107, 411, 413, 417, 434, and 438 exhibited no appreciable cytotoxic activity against KB (VJ300) cells.22,23,43,72 However, they possessed IC50 values of 0.39–38.7 μg mL−1 against KB (VJ300) cells in the presence of 0.1 μg mL−1 vincristine. Subramaniam et al. (2007) reported that kopsiloscine A (93), rhazinilam (409), especially two alkaloids rhazinal (407) and rhazinicine (408), showed inhibition to both KB, KB (VJ300), and KB (VJ300) + 0.1 μg mL−1 vincristine.32

Dimeric alkaloid norpleiomutine (282) exhibited cytotoxicity to PC-3, HCT-116, MCF-7, A-549, KB (VJ300), especially in terms of KB (VJ300) + 0.1 μg mL−1 vincristine, better than its analogous dimer kopsoffinol (289).19 This can be explained by the functionality of OH group at carbon C-19. Most Kopsia mersinines seem not to be anticancer agents. However, novel compounds 366–367 and 373–375 also established the significant cytotoxicity to reserve MDR in drug-resistant KB (VJ300) with the IC50 values of 3.2–11.2 μg mL−1.103 Valparicine (446) would be superior to the positive control vincadifformine in a cytotoxic assay against Jurkat cell growth.10 In addition, this compound and arboloscine (437) showed positive signals to resist the growth of KB (VJ300) and KB (VJ300) + 0.1 μg mL−1 vincristine (Table 2).10

3.2. Anti-microbial activity

Nowadays, microbial resistance to well-known antibiotics has caused major concern about the treatment of infectious diseases. A vast amount of studies has recently been conducted to determine possible answers. Phytochemicals have been shown to exhibit antibacterial activity against sensitive and resistant infections through various approaches. To have a look at the IZ (inhibitory zone) and MIC values of Kopsia constituents (Table 2), compounds 43–47, 48–53, and 76 are not only potential anticancer molecules but also useful antimicrobial agents.52,53 Especially, kopsiafrutine E (47) with the MIC values of 0.15–1.14 mM established a remarkable antimicrobial effect against twelve pathogenic microorganisms, including two Gram positive bacteria Staphylococcus aureus and S. epidermidis, five Gram negative bacteria Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Shigella dysenteriae, three fungi Candida albicans, C. tropicalis, and C. glabrata, and two oral pathogens Streptococcus mutans and S. viridans.52 Likewise, compounds 48–49 showed strong antimicrobial activity with MIC values of less than 0.3 mM against seven bacteria E. cloacae, E. coli, K. pneumoniae, P. aeruginosa, S. aureus, S. dysenteriae, and S. epidermidis.53

In another assessment, kopsiflorine (74) and kopsihainins D–F (85–87) showed suppression towards the Gram positive bacterium Staphylococcus aureus with IZ values ranging from 9.7 to 11.2 mm, but compounds 3, 17, 73, 109, 124, 405, and 406 were inactive.12 In an antimicrobial assay against E. coli, Erwinia carotovra, Bacillus subtilis, B. cereus, and S. aureus, two best agents N-decarbomethoxykopsamine (14) and N1-decarbomethoxy chanofruticosinic acid (206) were associated with the MIC values of 7.8–15.5 and 15.5–31.3 μg mL−1, respectively.7 These two molecules further showed antifungal activity against Rhizoctonia solani, Penicillium italicum, Fusarium oxysporum f. sp. Cubense, and F. oxysporum f. sp. Niveum (Table 2).7 Lastly, two eburnamines 19-hydroxy-(−)-eburnamonine (267) and phutdonginin (297) showed moderate activity against the growth of E. coli with the same MIC value of 32 μg mL−1.21

3.3. Anti-inflammatory activity

Inflammation is a part of the complicated biological reaction of living bodies to harmful stimuli such as irradiation, physical injury, metabolic stress, and infection.133–135 K. officinalis constituents are such useful agents to treat autoimmune diseases due to their inhibition of human T cell proliferation and proinflammatory cytokines.16 Indeed, K. officinalis constituents decarbomethoxykopsine (11), N(4)-methylkopsininate (170), 12-methoxychanofruticosinic acid (222), and rhazinilam (409) inhibited T cell growth with the IC50 values of 25.4, 21.6, 27.8, and 1.0 μM, respectively.16 The best molecule 409 also responded to the arrest in the G2/M phase of the T cell cycle and caused a decrease in IL-6 and IL-17 levels in activated T cells.16

The secretion of cytokines IL-1β and TNF-α or PGE2 levels has mainly caused inflammatory reactions. When LPS-stimulated RAW 264.7 cells, at the concentration of 5 μg mL−1, kopsia C (219), methyl N1-decarbomethoxychanofruticosinate (225), methyl 12-methoxychanofruticosinate (228), kopsiofficines I–J (279–280), (+)-O-methyleburnamine (290), (−)-O-methylisoeburnamine (291), and leuconodine D (439) have remarkable anti-inflammatory effects on IL-1β and TNF-α, and PGE2, and comparable with positive control dexamethasone at the concentration of 10 μg mL−1.75

3.4. Anti-allergic and antidiabetic activities

Naturally occurring compounds have been recognized as potential antiallergic agents. In an experiment against histamine and β-hexosaminidase in RBL-2H3 cells, the IC10 values of 3.73–11.78 μg mL−1 were assigned to four alkaloids kopsilarutensinine (90), kopsinine (126), (−)-eburnamine (257), and (−)-tetrahydroalstonine (448).66 In the same model against histamine and β-hexosaminidase in RBL-2H3 cells, in contrast to the MeOH extract of K. arborea leaves, the MeOH extracts of K. larutensis bark and root were found better than those of K. arborea bark and root (Table 2).66,129

For antidiabetic activity, among tested compounds for the high glucose-evoked podocyte injury inhibition, the EC50 values were orderly run as kopsinine 126 (3.0 μM) > leuconolam 405 (3.8 μM) > methyl 11,12-dimethoxychanofruticosinate 224 (10.2 μM) > 16α-hydroxy-19-oxoeburnamine 264 (12.0 μM) > reference compound astragaloside IV (15.4 μM) > 11-hydroxykopsilongine 29 (24.5 μM).25 However, four pauciflorine derivatives 11,12-demethoxy-16-deoxypauciflorine (379) and kopsioffines A–C (384–386) failed to suppress enzyme α-glucosidase (IC50 > 50 μM).109

3.5. AChE inhibitory, anti-manic, anti-tussive, and anti-nociceptive activities

In Alzheimer's disease treatment based AChE inhibitory examination, kopsamine (39) has the minimum inhibitory requirement (MIR) value of 12.5 μg, as compared with that of the reference compound galanthamine (MIR 0.004 μg).21 Meanwhile, two novel chanofruticosinates, kopsihainanines A–B (220–221), displayed weak AChE inhibitory activity with the respective IC50 values of 38.5 and 50.6 μM.6 (−)-12-Methoxykopsinaline (165) with the IC50 value of 12.5 mg mL−1, showed anti-manic activity in Drosophila.13

Kopsinine 126 (70 mg kg−1, i.p.) and methyl N1-decarbomethoxychanofruticosinate 225 (250 mg kg−1, i.p.) exhibited 88 and 76% cough inhibition in the antitussive assays when citric acid activated guinea pig cough model.65 In addition, anti-tussive effect of compound 126 was due to its interaction with δ-opioid receptors.65

The alkaloidal extract of K. macrophylla (400 mg kg−1, p.o.) was responsible for a decrease in the number of contortions and stretching via the peripheral mechanism in anti-nociceptive assays when acetic acid stimulated pain in mice, but it has no effect in anti-pyretic assay.130

3.6. Cardiovascular and vasorelaxant activities

Cardiovascular disease (CVD) refers to a group of illnesses affecting the heart and blood arteries. CVD is the largest cause of death worldwide with 17.9 million deaths (32.1%) in 2015.136 Drug discovery for CVD started from the 18th century at least.137 To consider Kopsia constituents for cardiovascular treatment, at doses of 0.2–10.0 mg kg−1 intravenous injection, kopsingine (112) caused decreases in arterial blood pressure and heart rate when hypertensive mice were anesthetized.123 However, kopsaporine (42) was reasonable for blood pressure increase, and kopsidine A (67) with the deletion of the methoxy group did not alter the responsible hypotension.123

Vasodilators can be used for cerebral vasospasm and hypertension treatments, as well as to enhance peripheral circulation.138,139 Flavisiamines A, C, and D (208 and 210–211), kopreasin A (216), methyl 11,12-methylenedioxychanofruticosinate (219), methyl N1-decarbomethoxychanofruticosinate (225), methyl 12-methoxy-N1-decarbomethoxychanofruticosinate (227), methyl 12-methoxychanofruticosinate (228), methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate (229), methyl 11,12-methylenedioxy-N1-decarbomethoxy-Δ14,15-chanofruticosinate (230), and prunifoline B (239) at the concentration of 3 × 10−5 M showed a moderate vasorelaxant effect of 14–41% when phenylephrine (3 × 10−7 M) precontracted rat aortic rings.84

4. Conclusion and future perspectives

To a certain extent, our comprehensive review establishes a panel of useful information on phytochemistry and pharmacology of the genus Kopsia. Since the 1950s, about nineteen Kopsia plants were used in phytochemical investigations, and more than four hundred seventy secondary metabolites have been isolated. Among 472 isolated compounds, monoterpene alkaloids (466 compounds) accounted for 98.73%. Kopsia monoterpene alkaloids have been fallen into about 30 structural skeletons, but aspidofractinines (204 compounds), eburnamines (48 compounds), and chanofruticosinates (37 compounds) predominated over. Various compounds were isolated from Kopsia plants for the first time. Many chemical classes of isolated compounds, such as mersinines and pauciflorines, can be seen as newly alkaloidal classes and were useful for chemotaxonomy. Some metabolites, such as kopsamine (39), kopsinine (126), (−)-eburnamine (257), (+)-isoeburnamine (274), rhazinilam (409), and (−)-tetrahydroalstonine (448), are characteristic metabolites of genus Kopsia. It also evidenced that Kopsia plant extracts and isolated compounds have induced a variety of pharmacological results, e.g., antimicrobial, anti-inflammatory, anti-diabetic, cardiovascular, vasorelaxant activities, especially cytotoxicity. With the great cytotoxic values, monoterpene alkaloids derived from Kopsia plants are promising anticancer agents in drug development programmes. However, studies on in vivo apoptotic mechanism, bioavailability, and metabolic approaches seem not available. To this end, no research was carried out to determine toxic effects of Kopsia plant extracts and their constituents. Therefore, it is necessary to deal with the extensive clinical studies to confirm the effects of Kopsia constituents on humans.

This review will be especially useful in offering fundamental insights into the medicinal usefulness of Kopsia plants. Furthermore, this evaluation can be used as a reference for clinical medication, long-term development, and plant consumption.

Abbreviations

HPLCHigh performance liquid chromatography
MSMass spectrum
CCColumn chromatography
IC50Half-maximal inhibitory concentration
IZInhibitory zone
MDRMultidrug resistance
MIRMinimum inhibitory requirement
MICMinimum inhibitory concentration
LPSlipopolysaccharide
AChEAcetylcholinesterase
NIH/3T3Normal mouse fibroblast cells
HL-60Human promyelocytic cells
HeLaHuman cervical cancer cells
HS-1, HS-4, SCL-1, and A-431Dermatoma cells
BGC-823Human gastric carcinoma cells
MCF-7Human breast cancer cells
W-480Colon cancer cells
HepG-2Human hepatocellular carcinoma cells; SMMC-7721 cells
SGC-7901Human gastric adenocarcinoma cells
SK-MEL-2Human skin cancer cells
SK-OV-3Ovarian cancer cells
A-549, 95-D, ATCC, H-446, H-460 and H-292, and SPCA-1Lung cancer cells
HT-29 and HCT-116Colorectal cancer cells
PC-3Human prostate cancer cells
JurkatHuman T lymphocyte cells
KBEpidermoid carcinoma cells

Conflicts of interest

The authors declare no conflict of interest, financial or otherwise.

References

  1. D. A. Williams, W. O. Foye and T. L. Lemke, Natural products. Foye's principles of medicinal chemistry, Lippincott Williams Wilkins, Philadelphia, 5th edn, 2002, ch. 1 Search PubMed.
  2. J. W. Kadereit and V. Bittrich, Flowering Plants. Eudicots, Springer, 2018 Search PubMed.
  3. J. Hu, X. Mao, L. Zhang, N. Jin, S. Yin, T. Peng and J. Shi, Chem. Nat. Compd., 2019, 55, 502–505 CrossRef CAS.
  4. T. S. Kam and O. S. Tan, Phytochemistry, 1990, 29, 2321–2322 CrossRef CAS.
  5. T. S. Kam, P. S. Tan and C. H. Chuah, Phytochemistry, 1992, 31, 2936–2938 CrossRef CAS.
  6. J. Chen, J. J. Chen, X. Yao and K. Gao, Org. Biomol. Chem., 2011, 9, 5334–5536 RSC.
  7. J. Chen, M. L. Yang, J. Zeng and K. Gao, Phytochem. Lett., 2014, 7, 156–160 CrossRef CAS.
  8. S. K. Wong, J. S. Y. Yeap, C. H. Tan, K. S. Sim, S. H. Lim, Y. Y. Low and T. S. Kam, Tetrahedron, 2021, 78, 131802 CrossRef CAS.
  9. T. He, Y. D. Wang, F. R. Li, S. Y. He, Q. M. Cui, Y. P. Liu, T. R. Zhao and G. G. Cheng, Biochem. Syst. Ecol., 2020, 93, 104159 CrossRef CAS.
  10. K. H. Lim, O. Hiraku, K. Komiyama, T. M. Koyano, M. Hayashi and T. S. Kam, J. Nat. Prod., 2007, 70, 1302–1307 CrossRef CAS PubMed.
  11. T. Z. Xie, Y. L. Zhao, W. G. Ma, Y. F. Wang, H. F. Yu, B. W. Wang, H. Z. Xin, P. F. Zhu, Y. P. Liu and X. D. Luo, Chin. J. Org. Chem., 2020, 40, 679–687 CrossRef CAS.
  12. Y. Yang, W. J. Zuo, Y. X. Zhao, W. H. Dong, W. L. Mei and H. F. Dai, Planta Med., 2012, 78, 1881–1884 CrossRef CAS PubMed.
  13. H. Zhou, H. P. He, N. C. Kong, Y. H. Wang, X. D. Liu and X. J. Hao, Helv. Chim. Acta, 2006, 89, 515–519 CrossRef CAS.
  14. J. J. Zheng, Y. L. Zhou and Z. H. Huang, Acta Chim. Sin., 1989, 2, 168–175 CrossRef.
  15. T. S. Kam, K. M. Sim, T. Koyano and K. Komiyama, Phytochemistry, 1999, 50, 75–79 CrossRef CAS.
  16. T. Zeng, X. Y. Wu, S. X. Yang, W. C. Lai, S. D. Shi, Q. Zou, Y. Liu and L. M. Li, J. Nat. Prod., 2017, 80, 864–871 CrossRef CAS PubMed.
  17. T. S. Kam and K. M. Sim, Phytochemistry, 1998, 47, 145–147 CrossRef CAS.
  18. T. S. Kam, G. Subramaniam and W. Chen, Phytochemistry, 1999, 51, 159–169 CrossRef CAS.
  19. W. S. Yap, C. Y. Gan, K. S. Sim, S. H. Lim, Y. Y. Low and T. S. Kam, J. Nat. Prod., 2016, 79, 230–239 CrossRef CAS PubMed.
  20. A. Guggisberg, T. R. Govindachari, K. Nagarajan and H. Schmid, Helv. Chim. Acta, 1963, 46, 679–683 CrossRef CAS.
  21. S. Cheenprachaa, A. Raksat, T. Ritthiwigrom and S. Laphookhieo, Nat. Prod. Commun., 2014, 9, 1441–1443 CrossRef.
  22. C. Y. Gan, K. Yoganathan, K. S. Sim, Y. Y. Low, S. H. Lim and T. S. Kam, Phytochemistry, 2014, 108, 234–242 CrossRef CAS PubMed.
  23. G. Subramaniam, O. Hiraku, M. Hayashi, T. Koyano, K. Komiyama and T. S. Kam, J. Nat. Prod., 2008, 71, 53–57 CrossRef CAS PubMed.
  24. M. Kitajima, M. Anbe, N. Kogure, S. Wongseripipatana and H. Takayama, Tetrahedron, 2014, 70, 9099–9106 CrossRef CAS.
  25. Z. W. Wang, C. R. Guo, Y. L. Lin, H. J. Yan, Y. Mu, Y. L. Geng, W. Liua and X. Wang, Fitoterapia, 2019, 137, 104258 CrossRef CAS PubMed.
  26. M. O. Hamburger, G. A. Cordell, K. Likhitwitayawuid and N. Ruangrungsi, Phytochemistry, 1988, 27, 2719–2723 CrossRef CAS.
  27. C. Kan-Fan, T. Sevenet, H. A. Hadi, M. Bonin, J. C. Quirion and H. P. Husson, Nat. Prod. Lett., 1995, 7, 283–290 CrossRef CAS.
  28. X. Z. Feng, C. Kan, H. P. Husson, P. Potie, S. K. Kan and M. Lounasmaa, J. Nat. Prod., 1984, 47, 117–122 CrossRef CAS.
  29. J. Zhu, A. Guggisberg and M. Hesse, Planta Med., 1986, 52, 63–64 CrossRef.
  30. T. S. Kam, Y. M. Choo, W. Chen and J. X. Yao, Phytochemistry, 1999, 52, 959–963 CrossRef CAS.
  31. T. S. Kam and Y. M. Choo, Phytochemistry, 2004, 65, 2119–2122 CrossRef CAS PubMed.
  32. G. Subramaniam, O. Hiraku, M. Hayashi, T. Koyano, K. Komiyama and T. S. Kam, J. Nat. Prod., 2007, 70, 1783–1789 CrossRef CAS PubMed.
  33. T. Varea, C. Kan, F. Remy, T. Sevene, J. C. Quirion, H. P. Husson and H. A. Hadi, J. Nat. Prod., 1993, 56, 2166–2169 CrossRef CAS.
  34. T. S. Kam, K. Yoganathan and S. L. Mok, Phytochemistry, 1997, 45, 789–792 CrossRef.
  35. K. Ahmad, Y. Hirasawa, A. E. Nugroho, A. H. A. Hadi and H. Morita, Heterocycles, 2012, 86, 1611–1619 CrossRef CAS.
  36. K. Ahmad, Y. Hirasawa, A. E. Nugroho, A. H. A. Hadi, K. Takeya, N. F. Thomas, K. Awang, H. Morita, T. S. Ping and M. A. Nafiah, Open Conf. Proc. J., 2013, 4, 75–82 CrossRef CAS.
  37. A. R. Battersby, J. C. Byrne, H. Gregory and S. P. Popli, J. Chem. Soc. C, 1967, 9, 813–819 RSC.
  38. A. R. Battersby and H. Gregor, J. Am. Chem. Soc., 1963, 16, 22–32 RSC.
  39. R. P. Glover, K. Yoganathan and M. S. Butler, Magn. Reson. Chem., 2005, 43, 483–485 CrossRef CAS PubMed.
  40. N. Ruangrungsi, K. Likhitwitayawuid, V. Jongbunprasert, D. Ponglux, N. Aimi, K. Ogata, M. Yasuoka, J. Haginiwa and S. Sakai, Tetrahedron Lett., 1987, 28, 3679–3682 CrossRef CAS.
  41. M. Sekiguchi, Y. Hirasawa, K. Zaima, T. C. Hoe, K. L. Chan and H. Morita, Heterocycles, 2008, 76, 867–874 CrossRef CAS.
  42. C. Q. Yang, Y. F. Ma and Y. G. Chen, Chem. Nat. Compd., 2017, 53, 595–597 CrossRef CAS.
  43. S. H. Lim, K. M. Sim, Z. Abdullah, O. Hiraku, M. Hayashi, K. Komiyama and T. S. Kam, J. Nat. Prod., 2007, 70, 1380–1383 CrossRef CAS PubMed.
  44. T. S. Kam, K. Yoganathan, C. H. Chuah and C. Wei, Phytochemistry, 1993, 32, 1343–1346 CrossRef CAS.
  45. T. S. Kam, K. Yoganathan and C. H. Chuah, Tetrahedron Lett., 1993, 34, 1819–1822 CrossRef CAS.
  46. T. S. Kam, T. M. Lim, G. Subramaniam, Y. M. Tee and K. Yoganathan, Phytochemistry, 1990, 50, 171–175 CrossRef.
  47. T. S. Kam and K. Yoganathan, Phytochemistry, 1996, 42, 539–541 CrossRef CAS.
  48. G. Subramaniam and T. S. Kam, Helv. Chim. Acta, 2008, 91, 930–937 CrossRef CAS.
  49. Halimatussakdiah, U. Amna, S. P. Tan, K. Awang, A. M. Ali, M. A. Nafiah and K. Ahmad, Int. J. Pharm. Sci. Rev. Res., 2015, 31, 89–95 CAS.
  50. Y. L. Zhou, Z. H. Huang, L. Y. Huang, J. P. Zhu, C. M. Li and G. L. Wu, Acta Chim. Sin., 1985, 1, 82–83 Search PubMed.
  51. T. S. Kam, L. Arasu and K. Yoganathan, Phytochemistry, 1996, 43, 1385–1387 CrossRef CAS.
  52. S. Y. Long, C. L. Li, J. Hu, Q. J. Zhao and D. Chen, Fitoterapia, 2018, 129, 145–149 CrossRef CAS PubMed.
  53. W. Q. Chia, Y. H. Jianga, J. Hub and J. Pan, Fitoterapia, 2018, 130, 259–264 CrossRef PubMed.
  54. Y. Wanga, L. Hang, L. Jiaoc, H. Liud and F. Li, Fitoterapia, 2017, 121, 53–57 CrossRef PubMed.
  55. T. Liu, J. Hu, J. X. Li and M. W. Chen, J. Asian Nat. Prod. Res., 2020, 22, 724–731 CrossRef CAS PubMed.
  56. X. D. Chen, J. Hu, J. X. Li and F. S. Chi, J. Asian Nat. Prod. Res., 2020, 22, 1024–1030 CrossRef CAS PubMed.
  57. K. Homberger and M. Hesse, Helv. Chim. Acta, 1982, 65, 2548–2557 CrossRef CAS.
  58. T. S. Kam, K. Yoganathan and K. H. Chuah, Phytochemistry, 1997, 45, 623–625 CrossRef CAS.
  59. S. K. Wong, S. P. Wong, K. S. Sim, S. H. Lim, Y. Y. Low and T. S. Kam, J. Nat. Prod., 2019, 82, 1902–1907 CrossRef CAS PubMed.
  60. T. S. Kam and G. Subramaniam, Nat. Prod. Lett., 1998, 11, 131–136 CrossRef CAS.
  61. M. C. Rho, M. Toyoshima, M. Hayashi, T. Koyano, G. Subramaniam, T. S. Kam and K. Komiyama, Planta Med., 1999, 65, 307–310 CrossRef CAS PubMed.
  62. T. S. Kam and Y. M. Choo, Tetrahedron Lett., 2003, 44, 1317–1319 CrossRef CAS.
  63. T. S. Kam and Y. M. Choo, Helv. Chim. Acta, 2004, 78, 991–998 CrossRef.
  64. J. Chen, X. Li, N. Li, J. Lu, X. Xu, H. Duan and L. Qin, Chem. Nat. Compd., 2012, 48, 834–835 CrossRef CAS.
  65. M. J. Tan, C. Yin, C. P. Tang, C. Q. Ke, G. Lin and Y. Ye, Planta Med., 2011, 77, 939–944 CrossRef CAS PubMed.
  66. M. S. Shahari, A. F. Ismail, E. Kumolosasi, N. F. Rajab and K. Husain, J. Innovations Pharm. Biol. Sci., 2017, 4, 80–86 CAS.
  67. A. Bhattacharya, A. Chatterjee and P. B. Bose, J. Am. Chem. Soc., 1949, 71, 3370–3372 CrossRef.
  68. K. Awang, M. Pais, T. Sevenet, H. Schaller, A. M. Nasir and A. H. A. Hadi, Phytochemistry, 1991, 30, 3164–3167 CrossRef CAS.
  69. X. Z. Feng, C. Kan, P. Potier, S. K. Kan and M. Lounasmaa, J. Med. Plants Res., 1983, 84, 280–282 CrossRef PubMed.
  70. T. S. Kam, P. S. Tan and C. Wei, Phytochemistry, 1993, 33, 921–924 CrossRef CAS.
  71. T. S. Kam, K. H. Lim, K. Yoganathan, M. Hayashi and K. Komiyama, Tetrahedron, 2004, 60, 10739–10745 CrossRef CAS.
  72. W. S. Yap, C. Y. Gan, Y. Y. Low, Y. M. Choo, T. Etoh, M. Hayashi, K. Komiyama and T. S. Kam, J. Nat. Prod., 2011, 74, 1309–1312 CrossRef CAS PubMed.
  73. T. S. Kam, K. Yoganathan and C. H. Chuah, Tetrahedron Lett., 1994, 35, 4457–4460 CrossRef CAS.
  74. T. S. Kam, K. Yoganathan and C. Wei, J. Nat. Prod., 1996, 59, 1109–1112 CrossRef CAS.
  75. T. Z. Xie, Y. L. Zhao, J. J. He, L. X. Zhao, X. Wei, Y. P. Liub and X. D. Luo, Fitoterapia, 2020, 143, 104547 CrossRef CAS PubMed.
  76. T. S. Kam and K. Yoganathan, Phytochemistry, 1997, 46, 785–787 CrossRef CAS.
  77. T. S. Kam and P. S. Tan, Phytochemistry, 1995, 39, 469–471 CrossRef CAS.
  78. K. H. Lim, Y. Y. Low, G. H. Tan, T. M. Lim and T. S. Kam, Helv. Chim. Acta, 2008, 91, 1559–1566 CrossRef CAS.
  79. K. Awang, O. Thoison, A. H. A Hadi, M. Païs and T. Sévenet, Nat. Prod. Lett., 1993, 3, 283–289 CrossRef CAS.
  80. T. S. Kam and K. Yoganathan, Nat. Prod. Lett., 1997, 10, 69–74 CrossRef CAS.
  81. K. Awang, T. Sévenet, M. Païs and A. H. A. Hadi, J. Nat. Prod., 1993, 56, 1134–1139 CrossRef CAS.
  82. K. H. Lim and T. S. Kam, Phytochemistry, 2008, 69, 558–561 CrossRef CAS PubMed.
  83. M. Sekiguchi, Y. Hirasawa, K. Zaima, T. H. Hoe, K. L. Chan and H. Morita, Heterocycles, 2008, 75, 2283–2288 CrossRef CAS.
  84. K. Zaima, Y. Matsuno, Y. Hirasawa, A. Rahman, G. Indrayanto, N. C. Zaini and H. Morita, Heterocycles, 2008, 75, 2535–2540 CrossRef CAS.
  85. J. F. Wang, Y. Wang, H. L. Wang, C. B. Xu and H. T. Wang, J. Asian Nat. Prod. Res., 2018, 21, 227–233 CrossRef PubMed.
  86. W. S. Chen, S. H. Li, A. Kirfel, G. Win and E. Breitmaier, Liebigs Ann. Chem., 1981, 1981, 1886–1892 CrossRef.
  87. T. S. Kam, P. S. Tan, P. Y. Hoong and C. H. Chuah, Phytochemistry, 1993, 32, 489–491 CrossRef CAS.
  88. K. Husain, I. Jantan, N. Kamaruddin, I. M. Said, N. Aimia and H. Takayama, Phytochemistry, 2001, 57, 603–606 CrossRef CAS PubMed.
  89. K. Husain, I. Jantan, I. M. Said, N. Aimi and H. Takayama, J. Asian Nat. Prod. Res., 2003, 5, 63–67 CrossRef CAS PubMed.
  90. Y. Wu, M. Kitajima, N. Kogure, Y. Wang, R. Zhang and H. Takayama, Chem. Pharm. Bull., 2010, 58, 961–963 CrossRef CAS PubMed.
  91. T. S. Kam, T. M. Lim, Y. M. Choo and G. Subramaniam, Tetrahedron Lett., 1998, 39, 5823–5826 CrossRef CAS.
  92. S. Uzir, A. M. Mustapha, A. H. A. Hadi, K. Awang, C. Wiart, J. F. Gallard and M. Pais, Tetrahedron Lett., 1997, 38, 1571–1574 CrossRef CAS.
  93. T. S. Kam, G. Subramaniam and C. Wei, Nat. Prod. Lett., 1998, 12, 293–298 CrossRef CAS.
  94. C. Kan, J. R. Deverre, T. Sevenet, J. C. Quirion and H. P. Husson, Nat. Prod. Lett., 1995, 7, 275–281 CrossRef CAS.
  95. Y. Wu, M. Kitajima, N. Kogure, Y. Wang, R. Zhang and H. Takayama, J. Nat. Med., 2009, 63, 283–289 CrossRef CAS PubMed.
  96. Y. Wu, M. Suehiro, N. Takahashi, M. Kitajima, N. Kogure, R. Zhang and H. Takayama, Chem. Nat. Prod., 2008, 50, 47–52 Search PubMed.
  97. Y. Wu, M. Kitajima, N. Kogure, R. Zhang and H. Takayama, Tetrahedron Lett., 2008, 49, 5935–5938 CrossRef CAS.
  98. N. Kogure, Y. Suzuki, Y. Wu, M. Kitajima, R. Zhang and H. Takayama, Tetrahedron Lett., 2012, 53, 6523–6526 CrossRef CAS.
  99. Y. Murakami, T. Koyama, Y. Suzuki, N. Takahashi, Y. Wu, N. Kogure, R. Zhang, M. Kitajima and H. Takayama, Chem. Nat. Prod., 2018, 56, 327–332 Search PubMed.
  100. M. Kitajima, T. Koyama, Y. Wu, N. Kogure, R. Zhan and H. Takayama, Nat. Prod. Commun., 2015, 10, 49–51 CrossRef PubMed.
  101. M. Kitajima, M. Nakazawa, Y. Wu, N. Kogure, R. P. Zhang and H. Takayama, Tetrahedron, 2016, 72, 6692–6696 CrossRef CAS.
  102. N. Kogure, R. Tokuda, S. Tooriyama, M. Nakazawa, T. Koyama, Y. Okamoto, Y. Mimori, Y. Wu, R. P. Zhang, M. Kitajima and H. Takayama, Chem. Nat. Prod., 2017, 24, 139–144 Search PubMed.
  103. G. Subramaniam, Y. M. Choo, O. Hiraku, K. Komiyama and T. S. Kam, Tetrahedron, 2008, 64, 1397–1408 CrossRef CAS.
  104. T. S. Kam and G. Subramaniam, Tetrahedron Lett., 2004, 45, 3521–3524 CrossRef CAS.
  105. T. S. Kam, G. Subramaniam and T. M. Lim, Tetrahedron Lett., 2001, 42, 5977–5980 CrossRef CAS.
  106. G. Subramaniam and T. S. Kam, Tetrahedron Lett., 2007, 48, 6677–6680 CrossRef CAS.
  107. G. Subramaniam, T. S. Kam and S. W. Ng, Acta Crystallogr., Sect. E: Struct. Rep. Online, 2003, 59, o555–o557 CrossRef CAS.
  108. Y. Y. Low, G. Subramaniam, K. H. Lim, R. C. S. W. Wong, T. Robinson and T. S. Kam, Tetrahedron, 2009, 65, 6873–6876 CrossRef CAS.
  109. Z. W. Wang, X. J. Shi, Y. Mu, L. Fang, Y. Y. Chen and L. Lin, Fitoterapia, 2017, 119, 8–11 CrossRef CAS PubMed.
  110. T. S. Kam, K. Yoganathan, T. Koyano and K. Komiyama, Tetrahedron Lett., 1996, 37, 5765–5768 CrossRef CAS.
  111. T. S. Kam, K. Yoganathan and C. Wei, Nat. Prod. Lett., 1996, 8, 231–235 CrossRef CAS.
  112. T. S. Kam, K. Yoganathan and C. Wei, J. Nat. Prod., 1997, 60, 673–676 CrossRef CAS.
  113. K. Homherger and M. Hesse, Helv. Chim. Acta, 1984, 67, 237–248 CrossRef.
  114. Y. Wu, M. Suehiro, M. Kitajima, T. Matsuzaki, S. Hashimoto, M. Nagaoka, R. Zhang and H. Takayama, J. Nat. Prod., 2009, 72, 204–209 CrossRef CAS PubMed.
  115. K. Awang, T. Sévenet, A. H. A. Hadi, B. David and M. Païs, Tetrahedron Lett., 1992, 33, 2493–2496 CrossRef CAS.
  116. T. S. Kam, K. Yoganathan and H. Y. Li, Tetrahedron Lett., 1996, 37, 8811–8814 CrossRef CAS.
  117. T. S. Kam, K. Yoganathan, K. H. Y. Li and N. Harada, Tetrahedron, 1997, 53, 12661–12670 CrossRef CAS.
  118. K. H. Lim and T. S. Kam, Helv. Chim. Acta, 2007, 90, 31–35 CrossRef CAS.
  119. K. H. Lim, Y. Y. Low and T. S. Kam, Tetrahedron Lett., 2006, 47, 5037–5039 CrossRef CAS.
  120. K. H. Lim, K. Komiyama and T. S. Kam, Tetrahedron Lett., 2007, 48, 1143–1145 CrossRef CAS.
  121. M. Kitajima, Y. Murakami, N. Takahashi, Y. Wu, N. Kogure, R. P. Zhang and H. Takayama, Org. Lett., 2014, 16, 5000–5003 CrossRef CAS PubMed.
  122. L. Y. Shan, T. C. Thing, T. S. Ping, K. Awang, N. M. Hashim, M. A. Nafiah and K. Ahmad, J. Chem. Pharm. Res., 2014, 6, 815–822 Search PubMed.
  123. G. B. Marini-Bettòlo, Ann. Ist. Super. Sanita, 1968, 4, 489–500 Search PubMed.
  124. J. H. Jiang, W. D. Zhang and Y. G. Chen, Trop. J. Pharm. Res., 2015, 14, 2325–2344 CrossRef CAS.
  125. K. Jewers, D. F. G. Pusey, S. R. Shama and Y. Ahmad, Planta Med., 1980, 38, 359–362 CrossRef CAS.
  126. A. R. Araujo, C. Kascheres, F. Fujiwara and A. J. Marsaioli, Phytochemistry, 1984, 23, 2359–2363 CrossRef CAS.
  127. T. Sevenet, L. Allorge, B. David, K. Awang, A. Hamid, C. Kan-Fan, J. C. Quirion, F. Remy, H. Schaller and L. E. Teo, J. Ethnopharmacol., 1994, 41, 1471–1483 CrossRef.
  128. B. Qin, Y. Wang, X. Wang and Y. Jia, Org. Chem. Front., 2021, 8, 369–383 RSC.
  129. M. S. Shahari, K. Husain, E. Kumolosasi and N. F. Rajab, Nat. Prod.: Indian J., 2017, 13, 1–7 Search PubMed.
  130. W. Reanmongkol, S. Subhadhirasakul, S. Thienmontree, K. Thanyapanit, J. Kalnaowakul and S. Sengsui, Songklanakarin J. Sci. Technol., 2005, 27, 509–516 Search PubMed.
  131. S. L. Mok, K. Yoganathan, T. M. Lim and T. S. Kam, J. Nat. Prod., 1998, 61, 328–332 CrossRef CAS PubMed.
  132. G. Z. Li, Y. H. Hu, D. Y. Li, Y. Zhang, H. L. Guo, Y. M. Li, F. Chen and J. Xu, Neurotoxicology, 2020, 81, 161–171 CrossRef CAS PubMed.
  133. N. T. Son, L. T. Anh, D. T. T. Thuy, N. D. Luyen, T. T. Tuyen, H. T. M. Duong and N. M. Ha, Nat. Prod. Commun., 2021, 16, 1–6 CrossRef.
  134. N. T. Son, L. T. Anh, D. T. T. Thuy, N. D. Luyen, T. T. Tuyen and P. T. Hai, Z. Naturforsch., C: J. Biosci., 2022, 77, 207–218 Search PubMed.
  135. N. T. T. Linh, N. T. T. Ha, N. T. Tra, L. T. T. Anh, N. V. Tuyen and N. T. Son, Mini-Rev. Med. Chem., 2021, 21, 273–287 CrossRef PubMed.
  136. H. Wang, M. Naghavi, C. Allen, R. M. Barber, Z. A. Bhutta and A. Carter, et al., Lancet, 2016, 388, 1459–1544 CrossRef.
  137. F. B. Alberti, Bull. Roy. Coll. Surg. Engl., 2013, 95, 168–169 CrossRef.
  138. S. Saponara, M. Durante, O. Spiga, P. Mugnai, G. Sgaragli, T. T Huong, P. N. Khanh, N. T. Son, N. M. Cuong and F. Fusi, Br. J. Pharmacol., 2016, 173, 292–304 CrossRef CAS PubMed.
  139. F. Fusi, M. Durante, G. Sgaragli, P. N. Khanh, N. T. Son, T. T. Huong and N. M. Cuong, Planta Med., 2015, 81, 298–304 CrossRef CAS PubMed.
This journal is © The Royal Society of Chemistry 2022
Click here to see how this site uses Cookies. View our privacy policy here.