jm6b00021_si_020.pdb (265.99 kB)
Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo
dataset
posted on 2016-05-05, 00:00 authored by Jun Yan, Jie Chen, Shun Zhang, Jinhui Hu, Ling Huang, Xingshu LiTwenty-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.