Synthesis and Biological Evaluation of 2-Substituted Benzyl-/Phenylethylamino-4-amino-5-aroylthiazoles as Apoptosis-Inducing Anticancer Agents.

Induction of apoptosis is a common chemotherapeutic mechanism to kill cancer cells The thiazole system has been reported over the past decades as a building block for the preparation of anticancer agents. A novel series of 2-arylalkylamino-4-amino-5-(3',4',5'-trimethoxybenzoyl)-thiazole derivatives designed as dual inhibitors of tubulin and cyclin-dependent kinases (CDKs) were synthesized and evaluated for their antiproliferative activity in vitro against two cancer cell lines and, for selected highly active compounds, for interactions with tubulin and cyclin-dependent kinases and for cell cycle and apoptosis effects. Structure-activity relationships were elucidated for various substituents at the 2-position of the thiazole skeleton. Among the synthesized compounds, the most active analogues were found to be the -chlorobenzylamino derivative as well as the -chloro and -methoxyphenethylamino analogues and , respectively, which inhibited the growth of U-937 and SK-MEL-1 cancer cell lines with IC values ranging from 5.7 to 12.2 μM. On U-937 cells, the tested compounds and induced apoptosis in a time and concentration dependent manner. These two latter molecules did not affect tubulin polymerization (IC > 20 μM) nor CDK activity at a single concentration of 10 μM, suggesting alternative targets than tubulin and CDK for the compounds.