Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity.
By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3',4',5'-trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel-Crafts reaction based on chemical modification of Combrestatatin A-4 (CA-4). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure-activity relationship study indicated that compound 8a with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series. 8a was found to exhibit the IC50 values of 8.4-26.4nM in five human cancer cell lines, with comparable inhibition effects to CA-4. Moreover, 8a showed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over-expressing multidrug resistant cell lines. Mechanism studies revealed that 8a could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent, 8a was also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore, 8a significantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that 8a was a promising microtubule targeting antitumor agent.
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Fang
F
Wang
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China.
Zhuang
Z
Yang
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Yibin
Y
Liu
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Liang
L
Ma
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China.
Yuzhe
Y
Wu
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Lin
L
He
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Mingfeng
M
Shao
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Kun
K
Yu
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Wenshuang
W
Wu
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Yuzhi
Y
Pu
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Chunlai
C
Nie
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: chenlijuan125@163.com.
Lijuan
L
Chen
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D013267:Stilbenes / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020533:Angiogenesis Inhibitors; D050256:Antimitotic Agents; D013267:Stilbenes; D013844:Thiazoles; D050257:Tubulin Modulators; C058728:fosbretabulin; D003078:Colchicine
Combrestatatin A-4; Diarylthiazole derivative; Microtubule; Tumor