title: Synthesis and biological evaluation of 2-amino-1-thiazolyl imidazoles as orally active anticancer agents.
abstract: 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.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli 35053, Taiwan.
authors.forename: Wen-Tai
authors.initials: WT
authors.lastname: Li
authors.forename: Der-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chen
authors.forename: Tung-Wei
authors.initials: TW
authors.lastname: Chen
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.forename: Jiunn-Jye
authors.initials: JJ
authors.lastname: Chuu
authors.forename: Tzu-Wen
authors.initials: TW
authors.lastname: Lien
authors.forename: Tsu-An
authors.initials: TA
authors.lastname: Hsu
authors.forename: Chen-Lung
authors.initials: CL
authors.lastname: Huang
authors.forename: Huan-Yi
authors.initials: HY
authors.lastname: Tseng
authors.forename: Chu-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Heng-Liang
authors.initials: HL
authors.lastname: Lin
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Chang
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine