[4-(imidazol-1-yl)thiazol-2-yl]phenylamines. A novel class of highly potent colchicine site binding tubulin inhibitors: synthesis and cytotoxic activity on selected human cancer cell lines.
Synthesis and cytotoxic activity in the submicromolar range of a series of [4-(imidazol-1-yl)thiazol-2-yl]phenylamines are described. Cell cycle dependent cytotoxicity on RKO human colon carcinoma cells with inducible expression of p27(kip1) and the influence on microtubule formation were investigated. Considering the significant correlation between the IC(50) values of tubulin polymerization inhibition, [(3)H]colchicine competition, and cytotoxicity of the investigated compounds, tubulin is the main cellular target. The inhibition of microtubule formation was shown to be mediated by interference with the colchicine binding site of tubulin. In depth analysis of the investigated compounds allowed the identification of modifications that altered the pharmacological profile of the compounds from a mitosis-inducing phenotype to a G1 cell cycle arresting phenotype.
Mahboobi
Siavosh
S
Department of Pharmaceutical Chemistry I, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de
Sellmer
Andreas
A
Höcher
Heymo
H
Eichhorn
Emerich
E
Bär
Thomas
T
Schmidt
Mathias
M
Maier
Thomas
T
Stadlwieser
Josef F
JF
Beckers
Thomas L
TL
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000814:Aniline Compounds; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine