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Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo.

Authors :
Jun Yan
Jie Chen
Shun Zhang
Jinhui Hu
Ling Huang
Xingshu Li
Source :
Journal of Medicinal Chemistry. Jun2016, Vol. 59 Issue 11, p5264-5283. 20p.
Publication Year :
2016

Abstract

Twenty-nine novel indole-chalcone derivatives were synthesized and evaluated for antiproliferative activity. Among them, 14k exhibited most potent activity, with IC50 values of 3-9 nM against six cancer cells, which displayed a 3.8-8.7-fold increase in activity when compare with compound 2. Further investigation revealed 14k was a novel tubulin polymerization inhibitor binding to the colchicine site. Its low cytotoxicity toward normal human cells and nearly equally potent activity against drug-resistant cells revealed the possibility for cancer therapy. Cellular mechanism studies elucidated 14k arrests cell cycle at G2/M phase and induces apoptosis along with the decrease of mitochondrial membrane potential. Furthermore, good metabolic stability of 14k was observed in mouse liver microsomes. Importantly, 14k and its phosphate salt 14k-P inhibited tumor growth in xenograft models in vivo without apparent toxicity, which was better than the reference compound CA-4P and 2. In summary, 14k deserves consideration for cancer therapy. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00222623
Volume :
59
Issue :
11
Database :
Academic Search Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
116231112
Full Text :
https://doi.org/10.1021/acs.jmedchem.6b00021