title: Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo.
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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Xingshu
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002599:Chalcone / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D002599:Chalcone; C030374:indole