Chalcone based azacarboline analogues as novel antitubulin agents: Design, synthesis, biological evaluation and molecular modelling studies

Sahil Sharma, Charanjit Kaur, Abhishek Budhiraja, Kunal Nepali, Manish K. Gupta, A. K. Saxena, P. M.S. Bedi

研究成果: 雜誌貢獻文章同行評審

29 引文 斯高帕斯(Scopus)

摘要

The present study involves the design of a series of 3-aryl-9-acetyl- pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 μM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 μM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.
原文英語
頁(從 - 到)648-660
頁數13
期刊European Journal of Medicinal Chemistry
85
DOIs
出版狀態已發佈 - 十月 6 2014
對外發佈Yes

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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