ABSTRACT
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.
Subject(s)
Aniline Compounds/chemical synthesis , Colchicine/metabolism , Thiazoles/chemical synthesis , Tubulin Modulators/chemical synthesis , Tubulin/metabolism , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Binding Sites , Cell Line, Tumor , Cell Shape/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
A nine-step (!) solid-phase synthesis and subsequent cleavage with cyclization from the polymeric support were the keys to preparing high-quality molecular libraries of thiazolylhydantoines 1 from modified amino acid building blocks. Each step in the synthesis is different. Because the final cyclization cleaves only molecules that have been successfully constructed, the products obtained are pure. R1 , R2 =alkyl; R3 =aryl, arylO; R4 =allyl.
