1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy.
The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon cancer cell lines and tubulin polymerization IC50 of 1.6 μM. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon cancer xenograft nude mice models, encouraging further study of this type of antitumor compound.
['Jiang|Junhang|J|', 'Zhang|Hao|H|', 'Wang|Chongqing|C|', 'Zhang|Qingsen|Q|', 'Fang|Shaoyu|S|', 'Zhou|Ruolan|R|', 'Hu|Jian|J|', 'Zhu|Ju|J|', 'Zhou|Youjun|Y|', 'Luo|Cheng|C|', 'Zheng|Canhui|C|']
D000818:Animals D000970:Antineoplastic Agents D001665:Binding Sites D005260:Female D045325:HCT116 Cells D006801:Humans D007191:Indazoles D008807:Mice, Inbred BALB C D008819:Mice, Nude D015394:Molecular Structure D011355:Prodrugs D011485:Protein Binding D012995:Solubility D014404:Tubulin D050257:Tubulin Modulators D023041:Xenograft Model Antitumor Assays
Colchicine site inhibitors X-ray co-crystal structure Water-soluble prodrug Cis-trans photoisomerization Microtubule-targeting agents