2. Academic Validation
  3. Design, Synthesis, and Evaluation of in Vitro and in Vivo Anticancer Activity of 4-Substituted Coumarins: A Novel Class of Potent Tubulin Polymerization Inhibitors

Design, Synthesis, and Evaluation of in Vitro and in Vivo Anticancer Activity of 4-Substituted Coumarins: A Novel Class of Potent Tubulin Polymerization Inhibitors

  • J Med Chem. 2016 Jun 23;59(12):5721-39. doi: 10.1021/acs.jmedchem.6b00158.
Dong Cao 1,  Yibin Liu 1,  Wei Yan 1,  Chunyu Wang 1,  Peng Bai 1,  Taijin Wang 1,  Minghai Tang 1,  Xiaoyan Wang 1,  Zhuang Yang 1,  Buyun Ma 2,  Liang Ma 3,  Lei Lei 1,  Fang Wang 1,  Bixue Xu 4,  Yuanyuan Zhou 1,  Tao Yang 1,  Lijuan Chen 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
  • 2 Department of Ultrasound, West China Hospital of Sichuan University , Chengdu, 610041, China.
  • 3 Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University , Chengdu, 610041, China.
  • 4 The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang, 550002, China.
PMID: 27213819 DOI: 10.1021/acs.jmedchem.6b00158
Abstract

In this paper, a series of novel 4-substituted coumarin derivatives were synthesized. Among these compounds 34, 39, 40, 43, 62, 65, and 67 exhibited significant antiproliferative activity toward a panel of tumor cell lines at subnanomolar IC50 values. Compound 65 showed potent antiproliferative ability (IC50 values of 7-47 nM) and retained full activity in multidrug resistant Cancer cells. Compound 65 caused G2/M phase arrest and interacted with the colchicine-binding site in tubulin, as confirmed by immune-fluorescence staining, microtubule dynamics assays, and competition assays with N,N'-ethylene-bis(iodoacetamide). Compound 65 reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, compound 65 significantly and dose-dependently reduced tumor growth in four xenografts models including paclitaxel sensitive and resistant ovarian tumors (A2780s and A2780/T), adrmicycin sensitive and resistant breast tumors (MCF-7 and MCF-7/ADR), suggesting that compound 65 is a promising novel antimitotic compound for the potential treatment of Cancer.

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