Design, synthesis and biological evaluation of a series of pyrano chalcone derivatives containing indole moiety as novel anti-tubulin agents

A new series of pyrano chalcone derivatives containing indole moiety were synthesized and evaluated for their antiproliferative activities. Among these compounds, 49b displayed the most potent cytotoxic activity against all tested cancer cell lines including multidrug resistant phenotype. Molecular...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 22; no. 7; pp. 2060 - 2079
Main Authors:	Wang, Guangcheng, Li, Chunyan, He, Lin, Lei, Kai, Wang, Fang, Pu, Yuzi, Yang, Zhuang, Cao, Dong, Ma, Liang, Chen, Jinying, Sang, Yun, Liang, Xiaolin, Xiang, Mingli, Peng, Aihua, Wei, Yuquan, Chen, Lijuan
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-04-2014
Subjects:	Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Cycle - drug effects Cell Proliferation - drug effects Chalcone Chalcone - analogs & derivatives Chalcone - chemical synthesis Chalcone - pharmacology Dose-Response Relationship, Drug Drug Design Drug Screening Assays, Antitumor Hep G2 Cells Humans Indole Indoles - chemistry Mice Mice, Inbred BALB C Mice, Nude Millepachine Models, Molecular Molecular Structure Neoplasms, Experimental - drug therapy Polymerization - drug effects Structure-Activity Relationship Tubulin Tubulin - chemistry Tubulin - metabolism Tubulin Modulators - chemical synthesis Tubulin Modulators - chemistry Tubulin Modulators - pharmacology Millepachine Tubulin Indole Chalcone
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Summary:	A new series of pyrano chalcone derivatives containing indole moiety were synthesized and evaluated for their antiproliferative activities. Among these compounds, 49b displayed the most potent cytotoxic activity against all tested cancer cell lines including multidrug resistant phenotype. Molecular docking analysis demonstrated the interaction of 49b at the colchicine binding site of tubulin. [Display omitted] A new series of pyrano chalcone derivatives containing indole moiety (3–42, 49a–49r) were synthesized and evaluated for their antiproliferative activities. Among all the compounds, compound 49b with a propionyloxy group at the 4-position of the left phenyl ring and N-methyl-5-indoly on the right ring displayed the most potent cytotoxic activity against all tested cancer cell lines including multidrug resistant phenotype, which inhibits cancer cell growth with IC50 values ranging from 0.22 to 1.80μM. Furthermore, 49b significantly induced cell cycle arrest in G2/M phase and inhibited the polymerization of tubulin. Molecular docking analysis demonstrated the interaction of 49b at the colchicine binding site of tubulin. In experiments in vivo, 49b exerted potent anticancer activity in HepG2 human liver carcinoma in BALB/c nude mice. These results indicated these compounds are promising inhibitors of tubulin polymerization for the potential treatment of cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2014.02.028