Synthesis and anticancer activity of dimeric podophyllotoxin derivatives
Zi, Cheng-Ting1,2,3; Yang, Liu2; Xu, Feng-Qing2; Dong, Fa-Wu2; Yang, Dan2; Li, Yan2; Ding, Zhong-Tao3; Zhou, Jun2; Jiang, Zi-Hua4; Hu, Jiang-Miao2
2018
发表期刊DRUG DESIGN DEVELOPMENT AND THERAPY
ISSN1177-8881
卷号12页码:3393-3406
摘要Background: Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for the development of antitumor drugs. Several podophyllotoxin-derived antitumor agents, including etoposide, are currently in clinical use; however, their therapeutic efficacy is often limited due to side effects and the development of resistance by cancer cells. Previous studies have shown that 4 beta-1,2,3-triazole derivatives of podophyllotoxin exhibit more potent anticancer activity and better binding to topoisomerase-II than etoposide. The effect of dimerization of such derivatives on the anticancer activity has not been studied. Methods: Two moieties of podophyllotoxin were linked at the C-4 position via 1,2,3-triazole rings to give a series of novel dimeric podophyllotoxin derivatives. 4 beta-Azido-substituted podophyllotoxin derivatives (23 and 24) were coupled with various dipropargyl functionalized linkers by utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to provide dimeric products in very good yield. The in vitro anticancer activity of the synthesized compounds was evaluated by MTT assay against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). The normal BEAS-2B (lung) cell line was also included for study in order to evaluate the cancer selectivity of the most active compound as compared with normal cells. Results: A group of 16 dimeric podophyllotoxin derivatives with different linkers were synthesized and structurally characterized. Most compounds do not show significant cytotoxicity (IC50 > 40 mM) against all five cancer cell lines. However, one compound (29) which bears a perbutyrylated glucose residue on the glycerol linker is highly potent against all five cancer cell lines tested, with IC50 values ranging from 0.43 to 3.50 mu M. This compound (29) also shows good selectivity towards cancer cell lines as compared with the normal BEAS-2B (lung) cell line, showing selectivity indexes from 4.4 to 35.7. Conclusion: The anticancer activity of dimeric podophyllotoxin derivatives is generally speaking not improved as compared to their monomeric counterparts, and the potency of these dimeric derivatives can be largely affected by the nature of the linker between the two moieties. Among the synthesized derivatives, compound 29 is significantly more cytotoxic and selective towards cancer cells than etoposide and cisplatin, which are currently in clinical use. Compound 29 is a promising anticancer drug and needs further studies.
关键词podophyllotoxin dimeric podophyllotoxin derivatives CuAAC reaction perbuty-tylated glucose antitumor synthesis
资助信息Yunnan province; National Key Research and Development Program of China
语种英语
资助项目Yunnan province[2015HB093] ; Yunnan province[2015FB168] ; National Key Research and Development Program of China[2017YFD0201402]
引用统计
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/62791
专题植物化学与西部植物资源持续利用国家重点实验室
通讯作者Jiang, Zi-Hua; Hu, Jiang-Miao
作者单位1.Yunnan Agr Univ, Coll Sci, Key Lab Pu Er Tea Sci, Minist Educ, Kunming 650201, Yunnan, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
3.Yunnan Univ, Sch Chem Sci & Technol, Minist Educ, Key Lab Med Chem Nat Resource, Kunming 650091, Yunnan, Peoples R China
4.Lakehead Univ, Dept Chem, 955 Oliver Rd, Thunder Bay, ON P7B 5E1, Canada
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GB/T 7714
Zi, Cheng-Ting,Yang, Liu,Xu, Feng-Qing,et al. Synthesis and anticancer activity of dimeric podophyllotoxin derivatives[J]. DRUG DESIGN DEVELOPMENT AND THERAPY,2018,12:3393-3406.
APA Zi, Cheng-Ting.,Yang, Liu.,Xu, Feng-Qing.,Dong, Fa-Wu.,Yang, Dan.,...&Hu, Jiang-Miao.(2018).Synthesis and anticancer activity of dimeric podophyllotoxin derivatives.DRUG DESIGN DEVELOPMENT AND THERAPY,12,3393-3406.
MLA Zi, Cheng-Ting,et al."Synthesis and anticancer activity of dimeric podophyllotoxin derivatives".DRUG DESIGN DEVELOPMENT AND THERAPY 12(2018):3393-3406.
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