Synthesis and bioevaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity.
A series of N,4-diaryl-1,3-thiazole-2-amines containing three aromatic rings with an amino linker were designed and synthesized as tubulin inhibitors and evaluated for their antiproliferative activity in three human cancer cell lines. Most of the target compounds displayed moderate antiproliferative activity, and N-(2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-amine (10s) was determined to be the most potent compound. Tubulin polymerization and immunostaining experiments revealed that 10s potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Moreover, 10s effectively induced SGC-7901 cell cycle arrest at the G2/M phase in both concentration- and time-dependent manners. The molecular docking results revealed that 10s could bind to the colchicine binding site of tubulin.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Maolin
M
Sun
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Qile
Q
Xu
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
Jingwen
J
Xu
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Yue
Y
Wu
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Yueting
Y
Wang
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
Daiying
D
Zuo
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Qi
Q
Guan
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.|Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Kai
K
Bao
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Jian
J
Wang
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
Yingliang
Y
Wu
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Weige
W
Zhang
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*
D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000622049:N-(2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-amine; D013844:Thiazoles; D050257:Tubulin Modulators