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Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan University, Kunming 650091, China
Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
* Author to whom correspondence should be addressed.
Received: 16 September 2013; in revised form: 4 November 2013 / Accepted: 5 November 2013 / Published: 13 November 2013
Abstract: A series of 4β-triazole-linked glucose podophyllotoxin conjugates have been designed and synthesized by employing a click chemistry approach. All the compounds were evaluated for their anticancer activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Most of these triazole derivatives have good anticancer activity. Among them, compound 35 showed the highest potency against all five cancer cell lines tested, with IC50 values ranging from 0.59 to 2.90 μM, which is significantly more active than the drug etoposide currently in clinical use. Structure-activity relationship analysis reveals that the acyl substitution on the glucose residue, the length of oligoethylene glycol linker, and the 4'-demethylation of podophyllotoxin scaffold can significantly affect the potency of the anticancer activity. Most notably, derivatives with a perbutyrylated glucose residue show much higher activity than their counterparts with either a free glucose or a peracetylated glucose residue.
Keywords: podophyllotoxin; 4β-triazole ring; click chemistry; anticancer activity
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MDPI and ACS Style
Zi, C.-T.; Xu, F.-Q.; Li, G.-T.; Li, Y.; Ding, Z.-T.; Zhou, J.; Jiang, Z.-H.; Hu, J.-M. Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings. Molecules 2013, 18, 13992-14012.
Zi C-T, Xu F-Q, Li G-T, Li Y, Ding Z-T, Zhou J, Jiang Z-H, Hu J-M. Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings. Molecules. 2013; 18(11):13992-14012.
Zi, Cheng-Ting; Xu, Feng-Qing; Li, Gen-Tao; Li, Yan; Ding, Zhong-Tao; Zhou, Jun; Jiang, Zi-Hua; Hu, Jiang-Miao. 2013. "Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings." Molecules 18, no. 11: 13992-14012.