Lauraceae alkaloids

Abstract

Lauraceae is one of the most representative botanical families, presenting 67 genera, with over 2500 species and more than 300 different alkaloids reported, mainly isoquinolines. Its diversity and relevance to chemosystematic relationships is presented and discussed.

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Dayana Lacerda Custódio

Dayana Lacerda Custódio obtained her BSc degree in Biological Sciences in 2006 from Universidade Estadual de Londrina, Brazil. In 2013 she received her PhD degree in Biotechnology, researching the alkaloids obtained from byproducts generated in the extraction of Aniba rosaeodora essential oil, at the Universidade Federal do Amazonas. Currently, she is a visiting researcher with a fellowship from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro at the Instituto Politécnico of Universidade do Estado do Rio de Janeiro.

Valdir Florêncio da Veiga Junior

Valdir Florêncio da Veiga Junior, completed his masters and PhD degrees in Natural Products Chemistry at Rio de Janeiro Federal University (UFRJ), Brazil, in 2004 under the supervision of Professor Angelo C. Pinto. He is currently associate professor of Biological Chemistry at the Amazonas Federal University (UFAM) and his research is focused on understanding the chemodiversity produced by Lauraceae, Burseraceae and Fabaceae botanical families. He is the leader of Q-BiomA, a research group on chemistry of Amazonian biomolecules.

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1 Introduction

The Lauraceae botanical family has a tropical and subtropical distribution, concentrated in Asian and American rainforests, including about 67 genera with over 2500 species. It is found particularly in countries with biodiversity hotspots. Brazil, for example, has a great number of representative species, with approximately 25 genera and 400 Lauraceae species. Lauraceae is considered one of the most important families in floristic composition in some of its forest ecosystems.^1,2

Several Lauraceae species have been used in the manufacture of various products with great economic value in areas such as the food and wood industries, for example, Ocotea porosa, the popular “Imbuia” and Ocotea odorifera, known as “Sassafras”. Additional, natural products found in species such as Aniba rosaeodora, with an essential oil rich in linalool, an excellent perfume fixative, possess high economic value in international markets.^3–6

However, some species' use is restricted to traditional communities, who possess empirical knowledge in the use of these plants.⁷ Many neolignans have been described in this family, and these substances have been used as lead compounds in new drug development.⁸ Together with neolignans and essential oils, this family presents several alkaloids, with isoquinolines as the main class reported in the literature.^9,10

The isoquinoline alkaloids are formed from the amino acid tyrosine by consecutive reactions forming the tetrahydroisoquinoline core (1, Fig. 1) and have a great importance due several pharmacological activities described to the benzyltetrahydroisoquinoline (2), aporphine (3), and pavine (4) skeletons. Another group of alkaloids present in Lauraceae are the indole alkaloids, which have benzopyrrolic structures where the indole (5) core is formed by the fusion of benzene and pyrrole rings at positions 2 and 3. When this link occurs at positions 3 and 4 of the pyrrole ring, the formation of the isoindole (6) core occurs. Structure numbering starts at the atom near the pyrrole ring junction, followed by other atoms around the indolic core.¹¹ Pyridine alkaloids, which are also found in this family, present a pyridine (7) ring that originates from nicotinic acid.¹²

Fig. 1 Classes of Lauraceae alkaloids.

2 Isoquinoline alkaloids

The isoquinoline alkaloids represent the majority of the alkaloids described in the Lauraceae family, and they have been reported in various genera. They stand out in Lauraceae due to their detection in several species and in various plant parts (Table 1).

Table 1 Distribution of the most common isoquinoline alkaloids from Lauraceae

Alkaloid	Genus	Species	Part of the plant	Reference
	Actinodaphne	obovata	Leaves and branches	13
	Cassytha	filiformis	Aerial part	14
				15
				16
				17
	Cinnamomum	insularimontanum	Roots	18
	Laurus	nobilis	Aerial part and root	19
	Litsea	sebifera	Leaves and branches	13
		laurifolia	Leaves	20
	Neolitsea	sericea	Leaves and stem bark	21
				22
		acuminatissima	Stem bark	23
	Actinodaphne	sesquipedalis	Stem bark	24
	Cassytha	filiformis	Aerial part	14
				16
				17
	Lindera	megaphylla	Roots	25
	Ocotea	brachybotra	Leaves	26
		macropoda		14
		minarum	Leaves	27
		macrophylla	Leaves	28
		puberula	Leaves	29
			Fruits	30
		vellosiana	Stem, leaves and fruits	31
	Aniba	muca	Stem bark	32
	Cassytha	filiformis	Aerial part	15
		pubescens		33
	Cryptocarya	chinensis	Leaves	34
	Lindera	angustifolia	Roots	35
	Litsea	petiolata	Stem bark	36
	Neolitsea	acuminatissima	Stem bark	23
	Ocotea	caesia	Stem	37
	Sassafras	albidum	Root bark	38
	Actinodaphne	nitida	Leaves	39
		pruinosa	Stem bark	40
	Alseodaphne	perakensis	Stem bark	41
	Cinnamomum	camphora	Roots	42
	Lindera	aggregata	Roots	43
		angustifolia	Roots	35
		chunii	Roots	44
	Litsea	laurifolia	Stem bark	20
		wightiana	Stem bark	13
		leefeana	Leaves	45
	Neolitsea	acuminatissima	Stem bark	23
		sericea	Stem bark and leaves	22
				21
	Phoebe	chinensis	Stem bark	46
		formosana	Stem bark	47
		grandis	Stem bark	48
		scortechinii	Stem bark	49
	Sassafras	albidum	Root bark	38
	Actinodaphne	nitida	Stem bark	39
		pruinosa	Stem bark	40
	Beilschmiedia	kunstleri	Stem bark	50
	Laurus	nobilis	Leaves	19
	Lindera	aggregata	Roots	43
		angustifólia	Roots	35
	Litsea	leefeana	Leaves	45
		sebifera	Leaves and branches	13
		wightiana	Stem bark	13
	Neolitsea	acuminatissima	Stem bark	23
		sericea	Stem bark and leaves	22
				21
	Ocotea	puberula	Leaves	29
	Phoebe	grandis	Stem bark	48
	Sassafras	albidum	Root bark	38
	Actinodaphne	obovata	Leaves and branches	13
	Beilschmiedia	kunstleri	Stem bark	50
	Cryptocarya	odorata	Stem bark	51
	Lindera	angustifolia	Roots	35
		benzoin	Branches	52
	Litsea	cubeba	Stem bark	53
		sebifera	Leaves and branches	13
	Neolitsea	sericea	Stem bark and leaves	22
				21
	Phoebe	chinensis	Stem bark	46
		grandis	Stem bark	48
	Actinodaphne	obovata	Leaves and branches	13
	Alseodaphne	perakensis	Stem bark	41
	Cryptocarya	odorata	Stem bark	51
	Lindera	angustifolia	Roots	35
		pipericarpa	Stem bark	54
	Litsea	cubeba		55
		cubeba	Stem bark	53
		sebifera	Leaves and branches	13
	Neolitsea	sericea	Stem bark and leaves	22
				21
	Aniba	muca	Stem bark	32
		rosaeodora	Stem	56
	Cinnamomum	camphora	Roots	42
	Cryptocarya	odorata	Stem bark	51
	Laurus	nobilis	Roots and aerial part	19
	Lindera	aggregata	Roots	43
	Litsea	laurifolia	Leaves	20
		leefeana	Leaves	45
		petiolata	Stem bark	36
	Neolitsea	acuminatissima	Stem bark	23
		sericea	Leaves	22
	Ocotea	duckei	Stem bark and leaves	57 and 58
		vellosiana	Fruits	31
	Phoebe	pittieri	Stem bark	59
	Sassafras	albidum	Root bark	38
	Cryptocarya	odorata	Stem bark	51
	Dehaasia	triandra	Leaves	60
	Lindera	pipericarpa	Stem bark	54
	Litsea	cubeba	Stem bark	53
	Ocotea	macrophylla	Stem	61
	Ocotea	vellosiana	Fruits	31

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The most frequently detected alkaloids in Lauraceae belong to the aporphinic group, with only one benzyltetrahydroisoquinoline. With methoxyls and only a few hydroxyl groups located at positions 1, 2, 8, 10 or 11, these alkaloids have similar structures and polarities: actinodaphnine (8), dicentrine (9), isoboldine (10), laurolitsine (norboldine) (11), boldine (12), laurotetanine (13) and N-methyllaurotetanine (14). The alkaloids actinodaphnine (8) and dicentrine (9) present a dioxymethylene at C-1 and C-2, whereas reticuline (15), a benzyltetrahydroisoquinoline alkaloid, also has two hydroxyls at C-7 and C-11, two methoxyls at C-6 and C-10 and a methyl at the nitrogen atom. Among the aporphine structures, actinodaphnine (8), laurolitsine (11), boldine (12), laurotetanine (13) and N-methyllaurotetanine (14) present a hydroxyl at C-9. Laurolitsine (11) has a methyl at C-10, whereas laurolitsine (11), boldine (12), laurotetanine (13), N-methyllaurotetanine (14) and isocorydine (16) have a methoxyl at C-1. Laurolitsine (11) and boldine (12) have a hydroxyl at C-2, and laurotetanine (13), N-methyllaurotetanine (14) and isocorydine (16) have a methoxyl at C-2.

Stem bark is the most common plant part where these alkaloids can be found in Lauraceae, together with leaves. Several studies have found these alkaloids in roots as well. Taking into account that almost all of these species are trees and not shrubs, it is important to note that the preference of performing a phytochemical study on roots indicates an objective approach based on a characteristic of the family.

Some of these alkaloids have been pharmacologically studied with promising activities for use in different health areas. High cytotoxicity was observed for actinodaphnine (8) using the Mel-5 and HL-60 cell lines.¹⁶ This alkaloid also induced apoptosis in the human hepatoma cells Mahlavu by increasing nitric oxide and reactive oxygen species and modulating NF-κB signalling.¹⁸

Dicentrine (9) showed cytotoxic activity in the HCE-6, Molt-4, CESS, HL60, K562 and MS-G2 cell lines.²⁵ Hoet et al.⁶² observed that dicentrine (9) presented activity against Trypanosoma brucei using in vitro assays. Recently, it was observed that this alkaloid has an antinociceptive effect following a pain stimulus (acetic acid) in experiments with mice.³⁰ This alkaloid also presented potent vasorelaxation in experiments conducted in mice, where the IC₅₀ ranged from 0.08 to 2.48 μM.¹⁷

Laurolitsine (11) showed cytotoxic activity against the Hep-2 cell line.⁴⁶ This substance also presented significant inhibitory activity against type I HIV integrase with an IC₅₀ of 16.3 μM.⁴⁴ Antiplasmodial activity against Plasmodium falciparum (clone 3D7) was also reported for this substance with an IC₅₀ of 1.49 mg mL⁻¹.⁶³

Boldine (12) showed antiinflammatory activity using a model of the oedema induced by carrageenan, in addition to antinociceptive activity.^64,65 This compound has also shown cytotoxic activity against Hep-2 tumour cells with total inhibition of the cell culture at a concentration of 0.3 mg mL⁻¹.⁶⁶

Morais et al.⁶⁷ performed neuropharmacological studies carried out with reticuline (15) in mice, observing that this alkaloid caused changes in sleep behaviour, motor coordination and conditioned avoidance responses in these animals, suggesting that this alkaloid possesses potent central nervous system depressant effects. Dias et al.⁶⁸ observed a blood pressure-lowering effect in rats, and Medeiros and coworkers⁵⁸ observed that this molecule induces vasorelaxation through the blockade of L-type Ca²⁺ channels.

The similarity of these substances and their pharmacological activities strongly indicates that further studies must be performed. These alkaloids are commonly obtained in very small quantities. Isolation on the gram scale would allow additional pharmacological experiments.

In addition to these substances, which are the most common alkaloids found in Lauraceae, there have been many other isoquinoline alkaloids described, with more restricted distribution. The genus Ocotea is one of the most studied in Lauraceae, with several alkaloids found, predominantly aporphines. In Ocotea macropoda, dicentrine (9), together with predicentrine (17, Fig. 2), ocopodine (18), nordicentrine (19), dehydrodicentrine (20), dehydroocopodine (21) and dicentrinone (22), was identified.^69,70 In O. macrophylla, isocorydine (16), (+)-natenine (23), glaucine (24) and dehydronantenine (25) were identified.⁶¹

Fig. 2 Ocotea isoquinoline alkaloids.

In recent studies performed on O. macrophylla leaves, the alkaloids dicentrine (9), (+)-nantenine (23), dehydronantenine (25), (+)-neolitsine (26, Fig. 3), (+)-N-acetyl-nornantenine (27), (+)-cassythidine (28) and didehydroocotein (29)²⁸ were isolated. From the stem, the alkaloids (S)-3-methoxynordomesticine (30), (S)-N-ethoxycarbonyl-3-methoxynordomesticine (31), (S)-N-formyl-3-methoxynordomesticine (32) and (S)-N-methoxycarbonyl-3-methoxynordomesticine (33) were also detected and identified. The alkaloid (S)-3-methoxynordomesticine (30) showed moderate antifungal activity against Fusarium oxysporum f. sp. lycopersici and antimicrobial activity towards Staphylococcus aureus 6538 and Enterococcus faecalis 29212.⁷¹ (+)-Nantenine (23) has also presented a reversible effect in muscle contraction and Ca²⁺ transients in experiments using rats.⁷²

Fig. 3 Ocotea isoquinoline alkaloids.

Extracts from the leaves of O. brachybotra yielded the alkaloids dicentrine (9), predicentrine (17), ocopodine (18), (±)-glaziovine (34, Fig. 4), cassythicine (35), leucoxine (36) and sinacutine (37). In the same study, the authors isolated morphinone derivatives such as pallidine (38), ocobotrine (39) and 14-episiomenine (40). Their structures were elucidated by the usual spectroscopy methods and chemical correlations.²⁶

Fig. 4 Ocotea isoquinoline alkaloids.

A great number of isoquinoline alkaloids have been reported in other species of Ocotea, including (+)-isoboldine (10), (−)-zenkerine (41, Fig. 5), (+)-laurelliptine (42), (−)-pulcine (43) and nororientidine (44), observed in O. caesia stems,³⁷ and 1-(p-methoxybenzoyl)-6,7-methylenedioxyisoquinoline (45), 1-(hydroxy-p-methoxybenzyl)-6,7-methylenedioxyisoquinoline (46), 1,2-dihydro-1-(p-methoxybenzoyl)-6,7-methylenedioxy-isoquinoline (47) and 1,2-dihydro-1-(hydroxy-p-methoxybenzyl)-6,7-methyl-enedioxyisoquinoline (48), obtained from O. pulchella stem bark.⁷³

Fig. 5 Ocotea isoquinoline alkaloids.

In Ocotea vellosiana, the alkaloids predicentrine (17), nordicentrine (19), ocoteine (49, Fig. 6), O-methylcassyfiline (50), leucoxylonine (51), ocotominarine (52) and reticuline (15) were detected in the branches; ocopodine (18) and ocominarine (53) in the leaves; glaucine (24), isocorydine (16) and corydine (54) in the fruits; and dicentrine (9) were identified in all plant parts studied.³¹ In Ocotea duckei were isolated the benzylisoquinoline alkaloids reticuline (15) from the leaves and stem bark^58,67 and coclaurine (55) from the stem.⁷⁴ Several aporphine structures were isolated from O. minarum leaves, which were identified as dicentrine (9), predicentrine (17), ocopodine (18), dicentrinone (22), leucoxine (36), ocoteine (49), leucoxilonine (51), ocotominarine (52), ocominarine (53), thalicminine (56), norleucoxilonine (57), isooconovine (58), 4-hydroxydicentrine (59) and ocominarone (60). Structure identification was performed by spectroscopy methods and chemical correlations.²⁷

Fig. 6 Ocotea isoquinoline alkaloids.

Investigations on O. glaziovii leaves have afforded assimilobine (61, Fig. 7), caaverine (62), liridinine (63) and glaziovine (34);⁷⁵ these compounds were also observed in O. variabilis.⁷⁶ This species has also shown the presence of nantenine (23), apoglaziovine (64) and variabiline (65).⁷⁶ In the species O. sinuata, nordomesticine (66) was found, while isocorydine (16), taliporfine (67), oconovine (68), ococriptine (69), ocoxilonine (70) and hernandonine (71) were identified in Ocotea, but without species recognition.^69,77,78

Fig. 7 Ocotea isoquinoline alkaloids.

A number of alkaloid structures have been elucidated in O. puberula: dicentrine (9), N-methyllaurotetanine (14), predicentrine (17), leucoxine (36), ocoteine (49), talicminime (56), isodomesticine (72, Fig. 8), dicentrine-N-oxide (73), dehydroocoteine (74), didehydroocoteine (75) and 3-hydroxydicentrine (76).^69,79–81 Further studies on the seedling leaves of Ocotea puberula have yielded dicentrine (9), boldine (12), leucoxine (36) and isodomesticine (72), in concentrations higher than those observed in the leaves of adult individuals.²⁹ The methanolic extract of O. leucoxylon yielded dicentrinone (22) as the major alkaloid besides dicentrine (9) and leucoxylonine (51).⁸² In the leaves of O. holdridgeiana, isocorydine (16), O,O-dimethylcorituberine (77), 3-hydroxynuciferine (78) and 3-methoxynuciferine (79) were identified.⁸³

Fig. 8 Ocotea isoquinoline alkaloids.

López and coworkers⁸⁴ obtained the alkaloids isocorydine (16), 3-hydroxynuciferine (78) and 3-hydroxy-6a,7-dihydronuciferine (80, Fig. 9) from ethanolic extracts of O. brenesii leaves. Studies performed with O. acutangula leaves led to the identification of (S)-(−)-pallidine (38), its derivative (S)-(−)-O-methylpallidine (81), as well as the alkaloids (S)-(−)-pallidinine (82) and (S)-(−)-O-methylpallidinine (83).⁸⁵

Fig. 9 Ocotea isoquinoline alkaloids.

From O. rodiaei stem bark, the structures of the alkaloids rodiasine (84, Fig. 10), ocoteamine (85), demerarine (86), norrodiasine, dirosine, otocamine and ocodemerine were elucidated.⁸⁶ Other alkaloids found in the genus Ocotea are talbaicalidine (87) in O. bucherii,⁸⁷ talictuberine (88) and 3-O-dimethyltalictuberine (89) in O. insularis.⁸⁸

Fig. 10 Ocotea isoquinoline alkaloids.

Most of these references on the Ocotea genus addressed are mentioned in the review about Ocotea aporphine alkaloids presented by Zanin and Lordello,³ in which the authors reported the occurrence of 54 aporphine alkaloids distributed in 17 species, including 39 aporphines, four oxoaporphines, five 6a,7-dehydroaporphines, one didehydroaporphine, one C-3-O-aporphine, one C-4-O-aporphine, two phenanthrenes and one proaporphine.

Recently, the alkaloids (+)-neolitsine (26), (+)-6S-ocoteine-N-oxide (90, Fig. 11), (+)-norocoxilonine (91) and (+)-talicsimidine (92) were isolated from the leaves and stem bark of Ocotea acutifolia.⁸⁹

Fig. 11 Ocotea isoquinoline alkaloids.

In Cryptocarya, several isoquinoline alkaloids have also been found. However, this genus presents several unusual pavine alkaloids. Among the exceptions are armepavine (93, Fig. 12), a benzylisoquinoline alkaloid obtained from Cryptocarya archboldiana leaves that represents 70% of the alkaloidal fraction obtained.⁹⁰ Other alkaloids present in the genus are (+)-orientaline (94) and laudanidine (95) in the stem bark of C. amygdalina,⁹¹ ateroline (96) and velucryptine (97) in C. velutinosa leaves⁹² and (+)-(1R,1Ra)-1a-hydroxymagnocumarine (98) from C. konishii.⁹³ Lisicamine (99) was isolated from the stem bark of Cryptocarya strictifolia.⁹⁴ In C. odorata stem bark, laurotetanine (13), N-methyllaurotetanine (14), reticuline (15), isocorydine (16) and cryptodorine (100) were found.⁵¹ From C. phyllostemom stem bark, two tetrahybenzylisoquinoline alkaloids, (+)-phyllocryptine (101) and (+)-phyllocryptonine (102) were obtained.⁹⁵

Fig. 12 Cryptocarya isoquinoline alkaloids.

The study of C. ferrea stems led to the isolation of three aporphine alkaloids: (−)-O-methylisopiline (103, Fig. 13), (+)-lirioferine (104) and (+)-norlirioferine (105).⁹⁶ Seven benzylisoquinoline alkaloids were obtained from C. rugulosa stem bark: (+)-reticuline (15), papraline (106), (+)-norcinnamolaurine (107), (+)-codamine (108), (+)-6-methoxy-1-(3′-methoxybenzyl)-N-methyl-7-isoquinolinol (109), (−)-N-methylisococlaurine (110) and (+)-reticuline-N-oxide (111).⁹⁷

Fig. 13 Cryptocarya isoquinoline alkaloids.

Cryptocarya chinensis is one of the most studied in this genus, with several alkaloids identified: isoboldine (10), (±)-romneine (112, Fig. 14), (−)-eschscholtzine (113), (+)-eschscholtzidine (114),⁹⁸ (−)-isocaryachine-N-oxide (115), isoboldine-β-N-oxide (116), 1-hydroxycryprochine (117), (+)-isocaryachine (118), (+)-caryachine (119), (−)-caryachine (120), (−)-isocaryachine (121), (−)-munitagine (122), bisnorargeminine (123),³⁴ all of them isolated from the leaves of this species.

Fig. 14 Cryptocarya isoquinoline alkaloids.

C. chinensis stems have yielded the pavine alkaloids (+)-eschscholtzidine (114), (+)-caryachine (119), (+)-escholtzidine-N-oxide (124, Fig. 15), (−)-12-hydroxyeschscholtzidine (125), (−)-12-hydroxycrychine (126), (−)-N-demethylcrychine (127), neocaryachine (128), crychine (129), (−)-argemonine (130), dorianine (131), (−)-N-demethyl-phelocryptine (132), in addition to the proaporphines cryprochine (133), isocryprochine (134), prooxocryptochine (135), isoamuronine (136) and (+)-8,9-dihydroestepharine (137).⁹⁹

Fig. 15 Cryptocarya isoquinoline alkaloids.

From the stem bark, (−)-eschscholtzidine (114), 1-hydroxycryprochine (117), (+)-caryachine (119), (−)-caryachine (120), (−)-isocaryachine (121), (−)-neocaryachine (128), (+)-cryprochine (133), (−)-isocaryachine-N-oxide B (138, Fig. 16), (−)-caryachine-N-oxide (139), 6,7-methylenedioxy-N-methylisoquinoline (140), (+)-isocaryachine-N-oxide (141), (+)-cinnamolaurine (142), (−)-mutagenine, 4-(6,7)-dimethyloxyisoquinoline-1-ylmethylphenol, (−)-2-O-norargemonine and (−)-N,N-dimethylcaryachine were isolated,^98,100,101 in addition to three quaternary pavine alkaloids N-methoxy salts of caryachine (143), neocaryachine (144) and crychine (145) isolated from C. chinensis callus culture.¹⁰² Caryachine was also obtained as an N-methoxy salt (143) by Chen et al.¹⁰³ from the stem bark of C. chinensis.

Fig. 16 Cryptocarya isoquinoline alkaloids.

A number of isoquinoline alkaloids have been reported in the genus Cassytha; the most studied species is Cassytha filiformis. Several alkaloids have been described to this species, including neolitsine (26), cassythidine (28), O-methylcassyfiline (=O-methylcassythine) (50), cassyfiline (=cassythine) (146, Fig. 17), lisicamine (99), cassamedine (147), cassameridine (148), launobine (149), bulbocapnine (150), (+)-nornuciferine (151), (+)-nuciferine (152), aterospermidine (153), liriodenine (154), O-methylateroline (155), catafiline (156), cataformine (157), isofiliformine (158), cassythic acid (159), norpredicentrine (160), (−)-O-methylflavinatine (=sebiferine) (161), (−)-salutaridine (162) and 1,7-methylenedioxy-3,10,11-trimethoxyaporphine (163).^14–17

Fig. 17 Cassytha isoquinoline alkaloids.

In Cassytha pubescens, the aporphine alkaloids isoboldine (10), nantenine (23), laurelliptine (42), nordomesticine (66), domesticine (164, Fig. 18) and sinoacutine (165) were identified.³³ Tsai and coworkers¹⁷ observed in this species dicentrine (9), neolitsine (26), cassythine (146) and cassythic acid (159). Cassythine (146) showed high activity against the cell lines Mel-5 (IC₅₀ of 24.3 μM) and HL-60 (IC₅₀ of 19.9 μM) and was also active in in vitro assays with Trypanosoma brucei.^16,62 Cytotoxic activity of neolitsine (26) was also observed in the cancer cell lines HeLa and 3T3 with an IC₅₀ of 21.6 μM and 21.4 μM, respectively.¹⁶

Fig. 18 Cassytha isoquinoline alkaloids.

Investigations into Aniba species afforded (R)-(+)-noranicanine (166, Fig. 19), a benzylisoquinoline trioxygenated alkaloid that was isolated from the stem bark of Aniba canellila.¹⁰⁴ Eleven other benzyltetrahydroisoquinoline alkaloids were also reported in this species, including four compounds monosubstituted on ring C with a hydroxyl at C-11, i.e. (−)-norcanelilline (167), (+)-canelilline (168), anicanine (169) and canelillinoxine (170); two compounds monosubstituted at C-9 in ring D, i.e. (−)-anibacanine (171) and (+)-manibacanine (172); two compounds monosubstituted at C-11 in ring D, i.e. (−)-pseudoanibacanine (173) and (+)-pseudoanibacanine (174); and three alkaloids with the same substitution pattern on rings A and B with a methyl group at positions 8α and 8β, i.e. (−)-α-8-methylpseudoanibacanine (175), (−)-β-8-methylpseudoanibacanine (176) and (−)-α-8-methylanibacanine (177).¹⁰⁵ Additionally, isoboldine (10), reticuline (15) and N-methylcoclaurine (178) were isolated from Aniba muca stem bark.³² Reticuline (15) was also found in Aniba rosaeodora.⁵⁶

Fig. 19 Aniba isoquinoline alkaloids.

In the genus Lindera, lindecarpine (179, Fig. 20) and N-methyllindecarpine (180) have been reported in Lindera pipericarpa roots,¹⁰⁶ and N-methyllaurotetanine (14), isocoridine (16) and norisocoridine (181) in the stem bark.⁵⁴ The bisbenzylisoquinoline dimer lindoldhamine (182) was isolated from leaves of L. oldhamii.¹⁰⁷ D-Dicentrine (9) was observed in L. megaphylla roots,²⁵ while laurotetanine (13) was obtained from L. benzoin branches.⁵² The alkaloids laurolitsine (11), hernandine (183), hernangerine (184), N-methylhernangerine (185), ocokryptine (N-methylhernandine) (186), hernandonine (187), 7-oxohernangerine (188), lindechunine A (189), lindechunine B (190) and 7-oxohernagine (191) were isolated from the roots of L. chunii.⁴⁴ Among the alkaloids found in L. chunii significant inhibitory activity against type I HIV integrase was observed for hernandonine (187), 7-oxohernangerine (188) and lindechunine A (189) with IC₅₀ of 7.7 μM, 18.2 μM and 21.1 μM, respectively.⁴⁴

Fig. 20 Lindera isoquinoline alkaloids.

More recently, some common aporphine alkaloids were observed in L. angustifolia roots, such as isoboldine (10), norboldine (11), boldine (12), laurotetanine (13), N-methyllaurotetanine (14), reticuline (15), norisocoridine (181), and N-ethoxycarbonyllaurotetanine (192, Fig. 21), in addition to magnocurarine (193).³⁵ In L. aggregata, the alkaloids laurolitsine (11), boldine (12), reticuline (15), (−)-pallidine (38), norisocoridine (181), linderaline (194), protosinomenine (195), laudanosoline 3′,4′-dimethylether (196), norisoboldine (197) and pronuciferine (198), together with the bisbenzylisoquinoline linderegatine (199) were isolated from the ethanolic extract of the roots.^43,108 Among these alkaloids, norisoboldine (197) has been reported to inhibit the production of proinflammatory cytokines in experiments with mouse macrophage cell lineage RAW 264.7.^43,109 For norisocoridine (181), antinociceptive activity and a high capacity for sequestering free radicals with an SC₅₀ of 14.1 mg mL⁻¹ have been found.⁶⁵

Fig. 21 Lindera isoquinoline alkaloids.

A number of structures are related to the genus Litsea, among then litebamine (200, Fig. 22), a phenanthrene alkaloid observed in L. cubeba stems, with the structure 3,7-dihydroxy-4,6-dimethoxy-N-methyl-tetrahydropyride [4,3-a]phenanthrene,¹¹⁰ N-methyllaurotetanine (14) and the quaternary alkaloids (−)-magnocurarine (193), (−)-oblongine (201), (−)-8-O-methyloblongine (202) and xantoplanine (203).^55,93 L. cubeba stem bark yielded five new isoquinoline alkaloids, i.e. (+)-N-(methoxycarbonyl)-N-nordicentrine (204), (+)-N-(methoxycarbonyl)-N-norpredicentrine (205), (+)-N-(methoxycarbonyl)-N-norglaucine (206), (+)-N-(methoxycarbonyl)-N-norbulbodione (207), (+)-N-(methoxycarbonyl)-N-norisocorydione (208) and (+)-8-methoxyisolaurenine-N-oxide (209), all obtained from the 70% ethanolic extract.¹¹¹ The alkaloids (+)-N-(methoxycarbonyl)-N-nordicentrin (204), (+)-N-(methoxycarbonyl)-N-norpredicentrine (205) and (+)-N-(methoxycarbonyl)-N-norglaucine (206) showed antimicrobial activity against the bacteria S. aureus and two fungi, A. alternata and C. nicotianae, while (+)-N-(methoxycarbonyl)-N-norbulbodione (207) and (+)-N-(methoxycarbonyl)-N-norisocorydione (208) exhibited significant cytotoxicity against six tested tumour cell lines.¹¹¹ Other alkaloids found in the stem bark of this species were (+)-laurotetanine (13), N-methyllaurotetanine (14) and isocorydine (16).⁵³

Fig. 22 Litsea isoquinoline alkaloids.

Some well-known alkaloids were also found in species of Litsea, such as isoboldine (10), laurelliptine (42) and liriodenine (154) in L. glutinosa leaves,¹¹² actinodaphnine (8), boldine (12), laurotetanine (13) and N-methyllaurotetanine (14) in L. sebifera leaves and branches, norboldine (laurolitsine) (11) and boldine (12) in L. wightiana stem bark¹³ and laurolitsine (11), boldine (12) and (+)-reticuline (15) in L. leefeana leaves.⁴⁵

A study on Litsea laurifolia led to the isolation of laurolitsine (11) from the bark and actinodaphnine (8), reticuline (15) and glaziovine (34) from the leaves.²⁰ From Litsea laeta stem bark, the alkaloids glaucine (24), laetanine (210, Fig. 23), laetine (211) and N,O-dimethylharnovine (212) were isolated.^113,114 In the same study, the authors isolated nordicentrine (19) and dicentrinone (22) from the leaves of Litsea salicifolia. Barbosa-Filho et al.⁶⁴ listed several alkaloids with antiinflammatory activity, including glaucine (24). Recently, a new bisbenzylisoquinoline alkaloid, lancifoliaine (213), was isolated from the stem bark of Litsea lancifolia, along with seven other known alkaloids: actinodaphnine (8), norboldine (11), boldine (12), reticuline (15), cassythicine (35), pallidine (38) and N-alyllaurolitsine (214).¹¹⁵ The alkaloids isoboldine (10), reticuline (15) and thalifoline (215) were isolated from L. petiolata bark.³⁶

Fig. 23 Litsea isoquinoline alkaloids.

In the genus Neolitsea, the alkaloids actinodaphnine (8), isoboldine (10), laurolitsine (11), boldine (12), reticuline (15), (−)-talicsimidine (92), (+)-cassythine (146), liriodenine (154), (+)-O-methylflavinatine (=sebiferine) (161), neolitacumonine (216, Fig. 24), (−)-norushinsunine (217), N-methylactinodaphnine (218), (−)-anonaine (219) and oxogalucine (220) were isolated from the stem bark of N. acuminatissima.²³ In Neolitsea sericea stems and leaves, actinodaphinine (8), isoboldine (10), laurolitsine (11), boldine (12), laurotetanine (13), N-methyllaurotetanine (14), reticuline (15), N-oxides of reticuline (111), norisocoridine (181), N-methylactinodaphinine (218), L-roemerine (221), litsericine (222), N-oxides of pallidine (223), boldine (224), juziphine (225) and N-methyllaurotetanine (226) were found, as well as (+)-corituberine (227).^{21,22,116–120} In the stem bark of Neolitsea variabillima, L-hernovine (228), L-nandigerine (229) and L-N-methylhernovine (230) were found.¹²¹

Fig. 24 Neolitsea isoquinoline alkaloids.

Among the isoquinoline alkaloids described in the genus Phoebe, laurolitsine (11), liriodenine (oxoushinsunine) (154), roemerine (221), ushinsunine (231, Fig. 25) and laurodionine (232) were isolated from the bark and stem of Phoebe formosana,^47,122 and some pentasubstituted aporphines were found in the bark of Phoebe molicella, i.e. norpurpureine (233), purpureine (234), preocoteine (235) and norpreocoteine (236).¹²³ From the leaves of Phoebe pittieri, the alkaloids lirioferine (104) and norlirioferine (105) were obtained.¹²⁴ Reticuline (15), norlirioferine (105), norpurpureine (233) and 1,2,3-trimethoxy-9,10-methylenodioxinorarporphine (237) were isolated in the bark of the same species.⁵⁹ In P. chinensis, several compounds with aporphine skeletons were obtained from the stem bark, including laurolitsine (11) and laurotetanine (13), very common structures in Lauraceae, as well as caaverine (62), liriodenine (154), sebiferine (=O-methylflavinatine) (161), anonaine (219) and roemerine (221).⁴⁶

Fig. 25 Phoebe isoquinoline alkaloids.

In Phoebe grandis, the phoebegrandines A (238, Fig. 26) and B (239), as well as phoebegrandine C, D and E were isolated from the leaves, while norboldine (11), boldine (12), laurotetanine (13), lindecarpine (179), (−)-grandine A (240), (−)-8,9-dihydrolinearisine (241), scortechiniines A and B (242) and lauroformine (243) were obtained from the stem bark.^48,125–127 In P. lanceolata stem bark, the alkaloids laurodionine (232) and nordelporphine (244) were identified, and were also observed in P. formosana stem bark.^122,128,129 In Phoebe scortechinii leaves, the dimer tryptamine proaporphine, (−)-phoebescortechiniine and phoebegrandines A (238) and B (239) were found,¹³⁰ while in the stem the aporphine norboldine (11) as well as the proaporphine alkaloids (+)-scortechiniine A and B (242), (−)-hexahydromecambrine A (245) and (−)-norhexahydromecambrine A (246) were identified.⁴⁹ Antiplasmodial activity against Plasmodium falciparum (clone 3D7) was reported for the alkaloids isolated from the stem bark of P. tavoyana, i.e. sebiferine (161) and roemerine (221), with IC₅₀ values of 2.76 mg mL⁻¹ and 0.89 mg mL⁻¹, respectively.⁶³

Fig. 26 Phoebe isoquinoline alkaloids.

Investigations into Dehaasia triandra afforded isocorydine (16) in the leaves, and some bisbenzylisoquinoline structures, including obaberine (247, Fig. 27), norobaberine (248), 3′,4′-dihydrostafasubine (249) and norisotetrandrine (250) were detected in stems of D. triandra.^60,131,132 Mukhtar et al.¹³³ studied the leaves of Dehaasia longipedicellata and isolated five morfinandienone alkaloids, including (−)-pallidine (38), (+)-pallidinine (82), (−)-sinoacutine (165), (+)-milonine (251) and (−) 8,4-dehydrosalutaridine (252).

Fig. 27 Dehaasia isoquinoline alkaloids.

From the stem bark of Actinodaphne pruinosa a new alkaloid was isolated, (+)-N-(2-hydroxypropyl)lindecarpine (253, Fig. 28), which showed cytotoxicity against P-388 leukaemia cells with an IC₅₀ of 3.9 μg mL⁻¹.⁴⁰ Additionally, the alkaloids (+)-norboldine (11), (+)-boldine (12), (+)-lindecarpine (179) and (+)-methyllindecarpine (180) were obtained.⁴⁰ In A. sesquipedalis, the presence of dicentrine (9) was reported in the stem bark,²⁴ while in A. nitida laurolitsine (11) and boldine (12) were found in the stem bark and leaves.³⁹

Fig. 28 Actinodaphne isoquinoline alkaloids.

Two morphinandienone structures were obtained from Beilschmiedia oreophila stems and bark, i.e. oreobiline (254, Fig. 29) and 6-epioreobiline.¹³⁴ From B. brevipes leaves, the benzylisoquinoline alkaloids (6,7-dimethoxy-4-methylisoquinolinyl)-(4′-methoxyphenyl)-metanone (255) and O,O-dimethylannocherine (256) were obtained.¹³⁵ Recently, in Beilschmiedia kunstleri, the alkaloids (+)-norboldine (11), (−)-pallidine (38) and (+)-N-methylisococlaurine (257) from leaves; (−)-isocaryachine (121), (+)-nornuciferine (151), noraterosperminine (258) and (+)-N-demethylphyllocaryptine (259) were isolated from stem bark; (+)-boldine (12), (+)-laurotetanine (13) and (+)-cassythicine (35) were obtained from vegetal parts.^50,136

Fig. 29 Beilschmiedia isoquinoline alkaloids.

In the genus Machilus, the alkaloid (+)-L-reticuline (15) was found in M. thumbergii, D,L-coclaurine (55) in M. kusanoi and M. macranta; (+)-L-laudanidine (95) in M. obovatifolia and M. arisanensis; (−)-L-N-noramepavine (260, Fig. 30) in M. kusanoi, M. pseudolongifolia, M. thumbergii, M. obovatifolia, M. arisanensis and M. zuihoensis; D,L-N-norarmepavine (261) in M. pseudolongifolia, M. thumbergii, M. obovatifolia, M. arisanensis and M. zuihoensis.^137–142 From M. glauscescens leaves, the oxoaporphine alkaloids machigline (1,2-methylenedioxy-9-hydroxy-10-methoxyoxoaporphine) (262) and ateroline (96) were obtained.¹⁴³

Fig. 30 Machilus isoquinoline alkaloids.

Studies performed on Alseodaphne species led to the identification of (+)-reticuline (15), a mixture of coclaurine (55) isomers in a proportion of 3 : 1 ((+)-coclaurine–(−)-coclaurine) and (−)-N-norarmepavine (261) in A. archboldiana,¹⁴⁴ whereas in A. semicarpifolia, the C-4 hydroxylated aporphine srilankine (263, Fig. 31) was obtained.¹⁴⁵ In A. corneri stem bark, a new bisbenzylisoquinoline alkaloid, 3′,4′-dihydronorstephasubine (264), together with two known structures, norstephasubine (265) and girolidine (266), were found; moderate vasorelaxation effects were identified for 264 and 266 in rat aorta assays.¹⁴⁶ From the roots of the same species, the bisbenzylisoquinoline alkaloids norstephasubine (265), (−)-girolidine (266), (+)-norlimacusine (267) and (+)-stephasubine (268) were isolated.¹⁴⁷

Fig. 31 Alseodaphne isoquinoline alkaloids.

Among the alkaloids described in Alseodaphne perakensis, N-methyl-2,3,6-trimethoxymorphinandien-7-one (269, Fig. 32) has been described as the main alkaloid in leaves, along with a mixture of other alkaloids in small quantities, including N-methyl-2,3,6-trimethoxymorphinandien-7-one-N-oxide (270).^148,149 From the stem bark of the same species, the alkaloids α′-oxoperakensimines A (271), B (272) and C (273) were isolated. In the same study, vasorelaxation activity was also reported for both substances using rat aorta assays.¹⁵⁰ Recently, a new alkaloid in this species was observed, also present in the stem bark, i.e. N-cyanomethylnorboldine (274), in addition to the known structures, N-methyllaurotetanine (14) and norboldine (11).⁴¹

Fig. 32 Alseodaphne isoquinoline alkaloids.

Some genera of Lauraceae have had a few reports regarding the occurrence of alkaloids in their species. For example, in Sassafras albidum root bark, common structures in Lauraceae, such as isoboldine (10), norboldine (11), boldine (12) and reticuline (15) have been described, as well as norcinnamolaurine (107) and cinnamolaurine (142).³⁸ Coclaurine (55), norcinnamolaurine (107) and corituberine (227) were isolated from the stems of Mezilaurus synandra.¹⁵¹ Le Quesne et al.¹⁵² obtained laurelliptine (42), an aporphine alkaloid, from the leaves and branches of Nectandra rigida. In Ravensara aromatica stem bark, the quaternary chloride base of N-methylisocorydine (275, Fig. 33) was observed.¹⁵³ From the ethanolic extract of Pleurothyrium cinereum leaves, the oxoaporphines thalicminine (56) and pleurotirine (276) were isolated.¹⁵⁴

Fig. 33 Ravensara isoquinoline alkaloids.

A number of common Lauraceae alkaloids have been found in Laurus nobilis, such as (+)-actinodaphinine (8), (+)-boldine (12), (+)-reticuline (15), (+)-neolitsine (26), (+)-isodomesticine (72), (+)-cryptodorine (100), (+)-launobine (149), (+)-N-methylactinodaphinine (218), (+)-nandigerine (229), (+)-norisodomesticine (277, Fig. 34) from the leaves; actinodaphnine (8), reticuline (15) and launobine (149) from the branches; and actinodaphnine (8), (+)-reticuline (15), (+)-launobine (149) and (+)-nandigerine (229) from the roots.¹⁹

Fig. 34 Laurus isoquinoline alkaloids.

Three related alkaloids were found in Licaria arminiaca stem bark, i.e. bracteoline (278, Fig. 35), O-methylbracteoline and α-dehydroreticuline (279); this was the first report of these structures in this genus.¹⁵⁵

Fig. 35 Licaria isoquinoline alkaloids.

3 Indole alkaloids

The indole substances reported in Lauraceae include cecilin (280, Fig. 36), a β-carboline alkaloid isolated from the trunk of Aniba santalodora¹⁵⁶ and triptophol-5-O-β-D-glycopiranoside (281), obtained from Ocotea minarum fruits.¹⁵⁷

Fig. 36 Aniba and Ocotea indole alkaloids.

In Litsea petiolata, two indole alkaloids were isolated from the bark, identified as aribine (=harmane) (282, Fig. 37) and norharmane (283).³⁶ Other β-carboline structures, i.e. the daibucarbolines A (284), B (285) and C (286), were obtained from Neolitsea daibuensis roots. In the same study, moderate antiinflamatory activity of daibucarboline A (284) was observed due to the inhibition of nitrite-producing cell lines, with an IC₅₀ of 18.41 μM.¹⁵⁸

Fig. 37 Litsea and Neolitsea indole alkaloids.

4 Pyridine alkaloids

Pyridine type alkaloids have been observed in Lauraceae, but with less frequency, as well as some indole alkaloids. In Aniba rosaeodora, the presence of two tertiary structures, anibine (287, Fig. 38)¹⁵⁹ and duckein (288),¹⁶⁰ has been reported, both obtained from the stem. Anibine (287) was also found in Aniba fragrans stems;¹⁶¹ this alkaloid was reported to possess analeptic activity.¹⁶²

Fig. 38 Aniba pyridine alkaloids.

5 Other classes of alkaloids

Besides isoquinoline, indole and pyridine alkaloids, the Lauraceae family also presents some other less common skeletons. Criptopleurine (289, Fig. 39), a phenanthroquinolizidine, was observed in C. laevigata and showed good activity against human nasopharyngeal epidermoid carcinoma (KB) cells with an IC₅₀ of 5.10 mg mL⁻¹.¹⁶³ The indolizidine quaternary alkaloid anibamine, elucidated as 6,8-didec-(1Z)-eni-5,7-dimethyl-2,3-dihydro-1H-indolizidine (290), was obtained from Aniba panurensis as a salt of trifluoroacetic acid¹⁶⁴ and from another Aniba species.¹⁶⁵

Fig. 39 Cryptocarya phenanthroquinolizidine and Litsea indolizidine alkaloids.

Dibenzopyrrolidine alkaloids cryptowoline (291, Fig. 40), O-methyl-cryptowoline (292), cryptowolinol (293) and cryptowolidine (294) were observed in Cryptocarya phyllostemon stem bark, while cryptaustoline (295) and cryptowolinol (293) were obtained from Cryptocarya oubatchensis stem bark and leaves.¹⁶⁶ In Litsea cubeba, two dibenzopyrrolidine structures, i.e. (−)-litcubine (296) and (−)-litcubinine (297), were isolated.¹⁶⁷

Fig. 40 Cryptocarya and Litsea dibenzopyrrolidine alkaloids.

Andrianaivoravelona et al.¹⁶⁸ isolated a tryptamine-derived alkaloid in a methanolic extract from the stem bark of Ravensara anisata, N-(p-coumaroyl)-tryptamine (298, Fig. 41).

Fig. 41 Ravensara tryptamine-derived alkaloid.

In Aniba riparia, the N-benzoyltyramines riparin I (299, Fig. 42), riparin II (300) and riparin III (301) were isolated.¹⁶⁹ Antimicrobial activity was reported for all three substances,¹⁷⁰ as well as antinociceptive activity for riparin I (299),¹⁷¹ anxiolytic activity for riparin II (300) and III (301), and antidepressant activity for riparin III (301), dependent on its interaction with serotonergic, noradrenergic and dopaminergic systems.^172–175 Castelo-Branco et al.¹⁷⁶ observed in pharmacological studies that the riparins I (299), II (300) and III (301) induced relaxation of contractions in guinea pig ileum and rat uterus produced by acetylcholine and histamine and oxytocin and bradykinin, respectively.

Fig. 42 Aniba N-benzoyltyramines alkaloids.

In a study performed on Machilus yaoshansis stem bark, two triterpene glycosylated alkaloids were isolated, machilaminoside A (302, Fig. 43) and machilaminoside B (303), as new substances in this species.¹⁷⁷

Fig. 43 Machilus triterpene glycosylated alkaloids.

Alkaloids receive great attention in research on natural products due to the variety of pharmacological activities they possess, which makes them indispensable ingredients for new drugs.¹⁷⁸ However, it is often infeasible to obtain these substances from their natural sources due to the low yields observed in extractions.¹⁷⁹ Even when it is possible to obtain them on a large scale from natural sources, high solvent consumption and length of time required make the process impracticable.¹⁷⁹ Thus, the synthesis of alkaloids has been a promising alternative for obtaining them, with several established routes, including procedures of metabolic engineering and biocatalysis.^180–183

Among the alkaloids observed in Lauraceae family, the synthesis of some structures is already described in the literature, such as that of actinodaphnine, boldine and isocorydine.^184–186 Techniques employing microorganisms to obtain molecules of interest are also reported, such as obtaining reticuline from simple carbon sources employing Escherichia coli and by fermentation of dopamine using Saccharomyces cerevisiae.^187–189 Some of these alkaloids are still used in the semi-synthesis of more complex alkaloids like litebamine and glaucine from boldine.^190,191

Combined molecular modelling and synthesis is an important tool in achieving most active alkaloids and derivatives in bulk. Studies of isoquinoline alkaloids, often reported in Lauraceae, showed that some structural characteristics favour the presence of pharmacological activity. Among them it was observed that replacement of hydroxyl by methoxyl groups, aromatization of the C-ring in protoberberine alkaloids and quaternary nitrogen all contribute to the increase of antipoliovirus, antiviral and acetylcholinesterase inhibitory activities of the alkaloids.^192,193 Moreover, the presence of 1,2-methylenedioxy groups and substituted groups in nitrogen appear to contribute to reduced alkaloid activity.^192,193

6 Conclusion

According to the data presented here, it can be seen that the Lauraceae family presents a great number of alkaloids of wide variety, with over 300 structures in 21 genera described in the literature. Isoquinoline alkaloids are reported as the major class, with about 287 compounds, as well as seven indoles, seven dibenzopyrrolidines, three pyridines, three benzoyltyamines, two glycoside triterpene alkaloids, one phenanthroquinolizidine, one indolizidine and one tryptamine derivative. The isoquinoline alkaloids are present in all genera reported in this review, and represent the major class in Lauraceae. However, other classes are reported in this family, some with only a few structures restricted to a specific genus.

Concerning the indole alkaloids, one structure has been mentioned in Aniba santalodora, one in Ocotea minarum, two in Litsea petiolata and three in Neolitsea daibuensis. Another class present in Lauraceae is the pyridine alkaloids, represented by two structures restricted to Aniba rosaeodora. Among the dibenzopyrrolidines, five structures are present in Cryptocarya oubatchensis and Cryptocarya phyllostemon and two have been reported in Litsea cubeba. Other alkaloid classes are also present in Lauraceae, such as the N-benzoyltyramines riparins I, II and III, observed in Aniba riparia, an indolizidine in Aniba panurensis, a quinolizidine in Cryptocarya laevigata, a tryptamine derivative in Ravensara anisata and two glycoside triterpene alkaloids in Machilus yaoshansis.

In order to evaluate a possible grouping taxonomic effect on the alkaloid composition, hierarchical cluster analysis (HCA) was performed using R software, version 3.0.1. Alkaloid frequency was analysed in the species according to data in the literature. In the HCA analysis, classes were separated into two groups. The first group was formed by Ocotea grouping with other genera that present major isoquinoline alkaloids, including Cassytha, Lindera and Phoebe (Fig. 44). These genera that have only isoquinoline alkaloids of different subclasses are soon expected to be grouped. The genus Ocotea is not in this group, but it is very close to it since this genus also presents an indole structure and several isoquinolines.

Fig. 44 HCA analysis of Lauraceae alkaloid classes.

The second largest group is formed by genera that present other classes besides isoquinolines in their composition, such as Ravensara, which presents a glycoside tryptamine derivative. Litsea and Cryptocarya are grouped together due to the presence of dibenzopyrrolidine structures found in both genera. Aniba and Machilus are grouped together due the presence of exclusive alkaloid classes in their composition, since Aniba presents pyridine and benzoyltyramine structures, and Machilus contains glycoside triterpene alkaloids.

The structures reported in this review predominantly belong to the isoquinoline class, which is composed of 287 structures distributed in all genera mentioned. The isoquinoline alkaloids were separated into subclasses with 148 aporphines, 47 benzylisoquinolines, 23 pavines, 21 proaporphines, 21 bisbenzylisoquinolines, 18 morphinandienones, five simple isoquinolines and four phenanthrene (Fig. 45). There are eight common isoquinoline structures, i.e. aporphine actinodaphnine (8), dicentrine (9), isoboldine (10), laurolitsine (norboldine) (11), boldine (12), laurotetanine (13), N-methyllaurotetanine (14) and isocorydine (16), and one benzylisoquinoline, reticuline (15), that are present in several species of Lauraceae (Fig. 2).

Fig. 45 Isoquinoline groups of alkaloids present in Lauraceae genera.

The genus Ocotea is the most studied, with 87 alkaloids described, including 86 isoquinolines and one indole. Ocotea minarum is the species with largest number of described isoquinoline structures, with 14 aporphine alkaloids. The Ocotea alkaloids are mostly aporphines, with 62 structures. Other genera rich in aporphine alkaloids are Cassytha, Lindera, Litsea, Neolitsea and Phoebe, with 27, 22, 23 and 19 structures, respectively.

Another genus with many reported structures is Cryptocarya, with 68 alkaloids, including 62 isoquinolines, five dibenzopyrrolidines and one quinolizidine. Cryptocarya chinensis is the most studied species in this genus, with 39 structures described, among them 23 pavine skeletons, a subgroup of isoquinoline alkaloids almost restricted to the genus Cryptocarya. The pavine structure (−)-isocaryachine (121) has also been observed in Beilschmiedia kunstleri.

Benzylisoquinoline alkaloids have been reported mainly in Aniba with 14 substances. This subclass is also present in Cryptocarya species, with 15 alkaloids reported, while the proaporphines are mostly found in Phoebe, with 12 structures present in Phoebe grandis and Phoebe scortechinii. The morphidianone structures are observed in more quantity in Ocotea and Dehaasia, with eight and five structures, respectively, while the bisbenzylisoquinolines are described mainly in Alseodaphne and Ocotea, with seven structures in each genus. Small quantities of other isoquinoline subclasses have also been observed, among them four phenanthrenes, one in Beilschmiedia, one in Litsea and two in Ocotea. Simple isoquinolines have been detected in Cryptocarya and Litsea, with four and one, respectively.

Pavine structures were observed in Cryptocarya and Beilschmiedia, while Dehhasia and Alseodaphne present bisbenzylisoquinoline alkaloids in high proportions when compared with other genera that possess this type of alkaloid. The genera Aniba, Machilus and Mezilaurus contain a number of benzylisoquinoline structures. On the other hand, the genus Phoebe presents a great quantity of proaporphine alkaloids. Other genera with small quantities of proaporphine alkaloids are Ocotea, Neolitsea and Lindera, with one structure each, and Cryptocarya, with six proaporphine alkaloids.

The genera Ravensara, Pleurothyrium and Nectandra have few aporphine alkaloids, while Cassytha and Laurus have mainly aporphines and a few structures belonging to the morphinandienone and benzylisoquinoline subclasses.

There are some genera with only few alkaloids described, such as Cinnamomum, Mezilaurus, Nectandra, Pleurothyrium and Ravensara, which have one to three alkaloids each. Perhaps these genera do not possess the biosynthetic routes to alkaloids in their secondary metabolism, or they are just less studied than other genera.

Some of these substances have restricted distribution, showing the possibility of their use as chemical markers, and therefore may play an important role in chemotaxonomy. Pharmacological properties have been observed, such as the cytotoxicity of actinodaphnine (8), dicentrine (9) and boldine (12) and the antiinflammatory effect of the latter, in addition to the potent central nervous system depressant effect observed for reticuline (15).

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra01904k

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