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
  • 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.