Synthesis and biological evaluation of 2-amino-1-thiazolyl imidazoles as orally active anticancer agents.
Designed from a high throughput screened hit compound, novel 2-amino-1-thiazolyl imidazoles were synthesized and demonstrated cytotoxicity against human cancer cells. 1-(4-Phenylthiazol-2-yl)-4-(thiophen-2-yl)-1H-imidazol-2-amine (compound 2), a 2-amino-1-thiazolyl imidazole, inhibited tubulin polymerization, interacted with the colchicine-binding sites of tubulins, and caused cell cycle arrest at the G(2)/M phase in human gastric cancer cells. Disruption of the microtubule structure in cancer cells by compound 2 was also observed. Compound 2 concentration-dependently inhibited the proliferation of cancer cells in histocultured human gastric and colorectal tumors. Given orally, compound 2 prolonged the lifespans of leukemia mice intraperitoneally inoculated with the murine P388 leukemic cells. We report 2-amino-1-thiazolyl imidazoles as a novel class of orally active microtubule-destabilizing anticancer agents.
Li
Wen-Tai
WT
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli 35053, Taiwan.
Hwang
Der-Ren
DR
Song
Jen-Shin
JS
Chen
Ching-Ping
CP
Chen
Tung-Wei
TW
Lin
Chi-Hung
CH
Chuu
Jiunn-Jye
JJ
Lien
Tzu-Wen
TW
Hsu
Tsu-An
TA
Huang
Chen-Lung
CL
Tseng
Huan-Yi
HY
Lin
Chu-Chung
CC
Lin
Heng-Liang
HL
Chang
Chung-Ming
CM
Chao
Yu-Sheng
YS
Chen
Chiung-Tong
CT
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism
D000970:Antineoplastic Agents; D007093:Imidazoles; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine