2. Academic Validation
  3. Synthesis and biological evaluation of 6H-pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones as antimitotic agents and inhibitors of tubulin polymerization

Synthesis and biological evaluation of 6H-pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones as antimitotic agents and inhibitors of tubulin polymerization

  • Bioorg Med Chem. 2014 Jan 15;22(2):848-55. doi: 10.1016/j.bmc.2013.12.004.
Tao Meng 1,  Wei Wang 2,  Zhixiang Zhang 2,  Lanping Ma 3,  Yongliang Zhang 1,  Zehong Miao 4,  Jingkang Shen 5
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
  • 3 Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China. Electronic address: lpma@simm.ac.cn.
  • 4 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China. Electronic address: zhm@jding.dhs.org.
  • 5 Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China. Electronic address: jkshen@simm.ac.cn.
PMID: 24360827 DOI: 10.1016/j.bmc.2013.12.004
Abstract

A series of 6H-pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones have been synthesized and evaluated for their antiproliferative activities. Among them, compounds 2j and 4d displayed potent cytotoxic activities in vitro against HeLa cell line with IC50 values of 0.07 and 0.06μM, respectively. In general, the antiproliferative activities are correlated with the inhibitory effect on tubulin polymerization and binding property of the colchicine binding site. In addition, flow cytometry and immunofluorescence analysis revealed selected compounds caused G2/M phase arrest of the cell cycle and disruption of the mitotic spindle assembly, which had correlation with proliferation inhibitory activity.

Keywords

6H-Pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones; Antitumor agents; Colchicine binding site; Inhibitors of tubulin polymerization.

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