Chemical Research in Chinese Universities ›› 2015, Vol. 31 ›› Issue (3): 372-380.doi: 10.1007/s40242-015-4435-5

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Discovery of Novel Tricyclic 5H-Pyridazino[4,5-b]indoles as Potent Antitumor Agents: Design, Synthesis and Biological Evaluation

ZHAI Xin, WANG Limei, SHI Jiyue, GONG Ping   

  1. Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
  • Received:2014-11-19 Revised:2014-12-04 Online:2015-06-01 Published:2014-12-22
  • Contact: GONG Ping E-mail:gongpinggp@126.com
  • Supported by:

    Supported by the National Natural Science Foundation of China(No.81273357) and the Liaoning Baiqianwan Talents Program, China(No.2013921042).

Abstract:

A novel series of 5H-pyridazino[4,5-b]indoles(L-01-L-32) was synthesized and characterized by means of 1H NMR, MS and elemental analysis. The cytotoxicity of the target compounds against Bel-7402 and HT-1080 cell lines were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. Most of them exhibited moderate to excellent cytotoxicity, and six compounds(L-04, L-06, L-18, L-20, L-21 and L-23) possessed dramatically increased cytotoxicity superior to Gefitinib. Of these initial hits, compound L-21 displayed remarkable cytotoxicity against the tested cell lines with half maximal inhibitory concentration(IC50) values of 4.6 and 2.1 μmol/L, respectively, which was 13.9- to 25.6-fold more potent than positive control.

Key words: 1-Anilino-5H-pyridazino[4,5-b]indole, EGFR inhibitor, Cytotoxicity