Discovery of a potent microtubule-targeting agent: Synthesis and biological evaluation of water-soluble amino acid prodrug of combretastatin A-4 derivatives.
Amino acid prodrugs are known to be very useful for improving the aqueous solubility of sparingly water soluble drugs (Drug Discovery Today 2013, 18, 93). Therefore, we synthesized eleven novel combretastatin A-4 amino acid derivatives and evaluated their anti-tumor activities in vitro and in vivo. Among them, compound 15 (valine attached to compound 3, which was shown to be a potent tubulin polymerization inhibitor in our previous study) exhibited high efficacy in tumor-bearing mice, and pharmacokinetic analysis in rats indicated that compound 15 was an effective prodrug as well. Besides, compound 15 significantly inhibited tubulin polymerization in vitro and in vivo by binding to the colchicine binding site. In addition, compound 15 induced cell cycle arrest in the G2/M phase and triggered apoptosis in a caspase-dependent manner. In conclusion, our study showed that compound 15 could have significant anti-tumor activity as a novel microtubule polymerization disrupting agent with improved aqueous solubility.
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Kun
K
Yu
School of Pharmacy, Chengdu University of TCM, Chengdu, Sichuan 611137, PR China.
Rong
R
Li
College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, PR China.
Zhuang
Z
Yang
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Fang
F
Wang
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Wenshuang
W
Wu
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Xiaoyan
X
Wang
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: niecl1022@scu.edu.cn.
Chunlai
C
Nie
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: chenlijuan125@163.com.
Lijuan
L
Chen
D000596:Amino Acids; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011355:Prodrugs; D051381:Rats; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*
D000596:Amino Acids; D000970:Antineoplastic Agents; D011355:Prodrugs; D013267:Stilbenes; C058728:fosbretabulin
Amino acid prodrug; Anti-tumor activity; Combretastatin A-4 derivatives; Microtubule targeted