Bo Zhang‡
ab,
Ruiying Guo‡c,
Yongzhou Huc,
Xiaowu Dongc,
Nengming Linb,
Xiaoyang Daia,
Honghai Wua,
Shenglin Ma*b and
Bo Yang*a
aZhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China. E-mail: yang924@zju.edu.cn; Tel: +86-57188208400
bTranslational Medicine Research Center, Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P. R. China. E-mail: mashenglin@medmail.com.cn; Tel: +86-57156007908
cZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China
First published on 21st June 2017
Natural products remain the largest resources of lead compounds that can be used to develop novel anticancer drug candidates. Based on deacetylisovaltratum, a natural product with promising anticancer activity, herein we designed and synthesized of a series of valepotriate derivatives with a novel skeleton from commercially available genipin. In addition, a structure–activity relationship study demonstrated the importance of an epoxy group on the C1-position and the preferable size of the sidechain ((5-methylhexanoyl)oxy) on the C-7 position of valepotriates for their cytotoxic activities. The most potent compound 1e showed moderate to good IC50 values against various cancer cells, ranging from 10.7 to 50.2 μM, which are comparable to that of deacetylisovaltratum. Additionally, we demonstrate that mitochondrion-mediated apoptosis would be its mechanism of action, thus enlightening the further development of novel valepotriate derivatives.
Valerian is a very important genus of plants used as a medicinal herb in many areas of the world, the roots and rhizomes of which have been used for the treatment of epilepsy, hysteria, nervous disorders, neurasthenia and emotional stress.5–9 In particular, Patrinia heterophylla Bunge, belonging to the genus Valerian, showed anticancer activity against metrocarcinoma and cervical cancer in ancient China, whereas the biological components responsible for its anticancer activity are not fully recognized.10,11 Indeed, a variety of pharmacologically active components (e.g. monoterpenes, valepotriates, and sesquiterpenes) have been isolated and characterized.12,13 Among them, valepotriates, belonging to the family of iridoids with a 10-carbon basic skeleton, showed their significant activity against cancer cells.1–3,14 Recently, we found that deacetylisovaltratum, a compound belonging to the class of valepotriates, could effectively cause G2/M-phase arrest in gastric cancer cells by disrupting tubulin polymerization, and inducing mitochondrion-dependent apoptosis.15,16 Considering the unique structure of epoxy group in deacetylisovaltratum, the alkylating properties could be responsible for its potent anti-cancer activity. Moreover, the structural diversity might change its physicochemical properties and also its intracellular activities. However, due to the lack of structural diversity in natural valepotriates, as well as the difficulty in synthetic procedures, the structural–activity relationship (SAR) studies of valepotriate analogues is very rare, which hampers the development of valepotriate as novel anti-cancer agents. Therefore, the exploration of the crucial structural requirement of valepotriates for anticancer activities is particularly needed. In this study, we intend to acquire series of valepotriate derivatives via semisynthesis and to study the biological activity of these compounds.
Recently, Murakami et al. reported the concise synthesis of 5,6-dihydrovaltrate from commercially available iridoid genipin, providing a novel semisynthetic route in structurally optimization of valepotriates (Fig. 2).17,18 As part of our continued interest in the area of chemical modification of natural products,19,20 herein, we designed, synthesized a series of valepotriate derivatives with novel skeleton from genipin using slightly modified Murakami's method. Noteworthy, some crucial SAR clues were found after investigating the effect of epoxy and length of aliphatic side chain on cytotoxicity against a variety of cancer cells. More significantly, some compounds showed superior cytotoxic activities than that of deacetylisovaltratum. In addition, mitochondrion-mediated apoptosis was significantly observed, which would be the exact action mechanism of its cytotoxic activities, thus enlightening the further development of novel valepotriate derivatives.
Cell lines | Cancer type | Cytotoxic activities, IC50 (μM) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
DI | 7a | 1a | 1b | 1c | 1d | 1e | 1f | 1g | 1h | ||
a N.T. indicates not detectable. | |||||||||||
SW1990 | Pancreatic cancer | 34.9 | 85.2 | 59.1 | >100 | 40.2 | 54.9 | 26.1 | N.T. | N.T. | N.T. |
BXPC3 | 14.4 | 24.6 | 48.2 | >100 | 28.1 | 37.1 | 25.1 | N.T. | N.T. | N.T. | |
CAPAN2 | 17.5 | 63.7 | 37.4 | 53.8 | 33.9 | 68.0 | 31.6 | 40.7 | >100 | >100 | |
CFPAC | 13.0 | 87.7 | 47.4 | 52.0 | 29.5 | 60.9 | 27.9 | 54.3 | 32.0 | 53.9 | |
PANC1 | 14.8 | >100 | 86.9 | N.T. | 48.0 | 66.9 | 20.6 | N.T. | N.T. | N.T. | |
BT474 | Breast cancer | 24.3 | N.T. | 97.8 | >100 | 21.4 | 54.0 | 50.2 | N.T. | N.T. | N.T. |
MCF7 | 27.5 | 51.2 | 77.4 | >100 | 18.1 | 19.8 | 10.7 | N.T. | N.T. | N.T. | |
MDA-MB-231 | 23.1 | 51.0 | 42.8 | >100 | 12.7 | 27.3 | 13.2 | N.T. | N.T. | N.T. | |
AGS | Gastric cancer | 7.7 | 53.2 | 26.3 | >100 | 28.9 | 36.9 | 22.9 | 55.7 | 59.5 | >100 |
HGC-27 | 14.8 | 25.7 | 47.5 | >100 | 20.9 | 28.2 | 21.5 | >100 | 54.0 | 26.6 | |
KATOIII | 32.2 | N.T. | N.T. | N.T. | N.T. | N.T. | N.T. | 48.8 | 51.2 | 92.5 | |
H1975 | Lung cancer | 14.3 | 21.0 | 25.8 | 93.0 | 28.2 | 15.9 | 11.3 | N.T. | N.T. | N.T. |
Compound 1a (26.6 mg, 43.2%): colorless oil 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 1.0 Hz, 1H), 6.11 (d, J = 5.6 Hz, 1H), 5.03 (dd, J = 7.7, 4.1 Hz, 1H), 3.73 (d, J = 3.1 Hz, 3H), 3.25 (d, J = 7.4 Hz, 1H), 3.06 (d, J = 4.6 Hz, 1H), 2.95 (d, J = 4.6 Hz, 1H), 2.86–2.75 (m, 1H), 2.37 (dd, J = 7.7, 5.6 Hz, 1H), 2.24 (t, J = 6.8 Hz, 2H), 2.10 (t, J = 6.1 Hz, 3H), 2.04–1.98 (m, 1H), 1.89 (dd, J = 14.8, 1.4 Hz, 1H), 0.96 (dd, J = 6.6, 1.8 Hz, 6H), 0.91 (d, J = 6.6 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 170.92, 170.04, 165.64, 150.33, 109.57, 87.30, 76.21, 75.26, 64.40, 50.41, 47.01, 42.25, 42.04, 41.74, 36.07, 29.85, 24.61, 24.59, 21.30, 21.24. LC-MS: 411 (M + H).
Compound 1b (28.5 mg, 51.6%): colorless oil 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 1.3 Hz, 1H), 6.12 (d, J = 5.8 Hz, 1H), 5.00 (dd, J = 7.7, 4.4 Hz, 1H), 3.74 (s, 3H), 3.25 (d, J = 7.7 Hz, 1H), 3.05 (d, J = 4.6 Hz, 1H), 2.97 (d, J = 4.6 Hz, 1H), 2.82 (dd, J = 7.8, 7.0 Hz, 1H), 2.59 (s, 3H), 2.34 (dd, J = 7.6, 5.9 Hz, 1H), 2.24 (dd, J = 7.1, 5.9 Hz, 2H), 2.15–2.06 (m, 1H), 1.90–1.83 (m, 1H), 0.96 (dd, J = 6.6, 1.9 Hz, 6H). LC-MS: 369 (M + H).
Compound 1c (27 mg, 41.2%): 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 1.2 Hz, 1H), 6.10 (d, J = 5.3 Hz, 1H), 5.01 (dd, J = 7.6, 3.8 Hz, 1H), 3.73 (s, 3H), 3.25 (dd, J = 13.5, 6.6 Hz, 1H), 3.06 (d, J = 4.6 Hz, 1H), 2.93 (d, J = 4.6 Hz, 1H), 2.80–2.73 (m, 1H), 2.39 (dd, J = 7.6, 5.3 Hz, 1H), 2.23 (dd, J = 15.4, 8.6 Hz, 3H), 2.10 (m, 1H), 1.91 (ddd, J = 14.9, 5.3, 3.9 Hz, 1H), 1.79 (s, 2H), 1.70 (s, 2H), 1.62 (d, J = 9.5 Hz, 1H), 1.57 (d, J = 4.1 Hz, 3H), 1.40–1.31 (m, 2H), 0.96 (dd, J = 6.6, 1.9 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 174.83, 171.08, 166.65, 151.35, 110.59, 88.27, 77.23, 76.24, 65.55, 51.41, 48.01, 43.06, 42.85, 37.02, 30.93, 28.79, 28.75, 25.66, 25.62, 25.35, 25.31, 22.26. LC-MS: 437 (M + H).
Compound 1d (24 mg, 37.2%): colorless oil 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J = 8.3, 1.2 Hz, 2H), 7.56 (s, 1H), 7.49 (d, J = 1.3 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 6.20 (d, J = 5.1 Hz, 1H), 5.30 (s, 1H), 3.67 (s, 3H), 3.33 (dt, J = 7.7, 6.4 Hz, 1H), 3.12 (d, J = 4.5 Hz, 1H), 3.04 (d, J = 4.5 Hz, 1H), 2.90–2.81 (m, 1H), 2.48 (dd, J = 7.6, 5.2 Hz, 1H), 2.25 (t, J = 6.9 Hz, 2H), 2.18–2.07 (m, 2H), 0.96 (dd, J = 6.6, 3.5 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 171.14, 166.60, 165.41, 151.32, 133.31, 129.67, 128.43, 110.70, 88.25, 77.43, 77.23, 65.72, 51.40, 48.20, 43.07, 37.02, 31.17, 25.65, 22.26. LC-MS: 431 (M + H).
Compound 1e (30 mg, 44.2%): colorless oil 1H NMR (500 MHz, CDCl3) δ 7.42 (s, 1H), 6.10 (d, J = 5.3 Hz, 1H), 5.05 (dt, J = 7.5, 3.8 Hz, 1H), 3.73 (d, J = 2.4 Hz, 3H), 3.26 (dd, J = 13.7, 7.3 Hz, 1H), 3.06 (dd, J = 4.5, 2.2 Hz, 1H), 2.91 (d, J = 4.6 Hz, 1H), 2.78 (dtd, J = 10.6, 7.8, 2.9 Hz, 1H), 2.41–2.36 (m, 1H), 2.28–2.20 (m, 2H), 2.20–2.14 (m, 1H), 2.10 (dt, J = 13.6, 6.8 Hz, 1H), 1.93–1.86 (m, 1H), 1.56–1.36 (m, 4H), 1.30–1.25 (m, 2H), 1.21–1.12 (m, 2H), 0.99–0.94 (m, 6H), 0.89–0.78 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 175.15, 175.07, 171.07, 166.64, 151.38, 110.60, 88.29, 88.28, 77.25, 76.28, 76.22, 65.62, 51.42, 48.08, 48.05, 47.35, 47.19, 43.06, 42.88, 37.17, 31.58, 31.51, 31.05, 29.53, 29.52, 25.61, 25.32, 25.27, 22.57, 22.51, 22.27. LC-MS: 453 (M + H).
Compound 1f (30 mg, 47.2%): colorless oil 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 1.3 Hz, 1H), 6.11 (d, J = 5.6 Hz, 1H), 5.02 (dd, J = 7.7, 4.2 Hz, 1H), 3.74 (s, 3H), 3.25 (d, J = 7.6 Hz, 1H), 3.05 (d, J = 4.6 Hz, 1H), 2.95 (dd, J = 9.8, 5.2 Hz, 2H), 2.85–2.75 (m, 1H), 2.36 (dd, J = 7.7, 5.7 Hz, 1H), 2.26–2.19 (m, 4H), 2.14–2.06 (m, 1H), 1.87 (ddd, J = 14.8, 5.9, 4.3 Hz, 1H), 1.68 (s, 1H), 1.57–1.52 (m, 2H), 1.34 (dd, J = 7.4, 3.6 Hz, 2H), 0.96 (dd, J = 6.6, 2.0 Hz, 6H), 0.89–0.86 (m, 3H). LC-MS: 425 (M + H).
Compound 1g (15 mg, 22.1%): colorless oil 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 1.1 Hz, 1H), 6.11 (d, J = 5.6 Hz, 1H), 5.01 (dd, J = 7.7, 4.2 Hz, 1H), 3.74 (s, 3H), 3.25 (d, J = 7.5 Hz, 1H), 3.05 (d, J = 4.6 Hz, 1H), 2.95 (d, J = 4.7 Hz, 2H), 2.85–2.76 (m, 1H), 2.36 (dd, J = 7.6, 5.8 Hz, 1H), 2.28–2.18 (m, 4H), 2.14–2.07 (m, 1H), 1.87 (ddd, J = 14.8, 5.8, 4.4 Hz, 1H), 1.67 (td, J = 14.5, 7.0 Hz, 1H), 1.58–1.50 (m, 2H), 1.25 (d, J = 4.0 Hz, 7H), 0.96 (dd, J = 6.6, 2.0 Hz, 6H), 0.87 (t, J = 6.9 Hz, 3H). LC-MS: 453 (M + H).
Compound 1h (18 mg, 25.0%): colorless oil 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 1.1 Hz, 1H), 6.11 (d, J = 5.7 Hz, 1H), 5.01 (dd, J = 7.7, 4.2 Hz, 1H), 3.73 (s, 3H), 3.29–3.19 (m, 1H), 3.05 (d, J = 4.6 Hz, 1H), 2.95 (d, J = 4.6 Hz, 1H), 2.81 (dt, J = 15.4, 7.9 Hz, 1H), 2.36 (dd, J = 7.6, 5.8 Hz, 1H), 2.26–2.19 (m, 4H), 2.10 (dt, J = 13.6, 6.8 Hz, 1H), 1.87 (ddd, J = 14.8, 5.8, 4.4 Hz, 1H), 1.57–1.50 (m, 2H), 1.25 (s, 12H), 0.96 (dd, J = 6.6, 2.0 Hz, 6H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.67, 171.06, 166.68, 151.33, 110.64, 88.36, 77.23, 76.28, 65.38, 51.45, 47.97, 43.08, 42.74, 37.10, 34.25, 31.85, 30.82, 29.40, 29.25, 29.22, 29.09, 25.62, 24.79, 22.66, 22.27, 22.25, 14.10. LC-MS: 481 (M + H).
Footnotes |
† Electronic supplementary information (ESI) available: NMR spectra of the synthesized compounds. See DOI: 10.1039/c6ra27478a |
‡ These authors contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2017 |