Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones

Cyclization of substituted thiosemicarbazones with a-bromo-4-cyanoacetophenone allows rapid singlestep sustainable syntheses of 4-cyanophenyl-2-hydrazinylthiazoles libraries (30 examples, 66-79%). All show anticancer efficacy against HCT-116 and MCF-7 carcinoma cell lines with the majority being more active than cisplatin positive controls. The compounds 2-(2-(2-hydroxy-3-methylbenzylidene) hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-((pentafluorophenyl)methylene)-hydrazinyl)-4-(4-cyanophenyl)thiazole (3a ') show optimal GI50 values (1.0 +/- 0.1 mM and 1.7 +/- 0.3 mM) against MCF-7 breast cancer cells. Against colorectal carcinoma HCT-116 cells, (2-(2-(3-bromothiophen-2-yl) methylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3b '), 2-(2-(2-hydroxy-3-methylbenzylidene) hydrazinyl)-4-(4-cyanophenyl)thiazole (3f), 2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4-(4-cyanophenyl) thiazole (3n) and 2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3w) are the most active (GI50 values: 1.6 +/- 0.2, 1.6 +/- 0.1, 1.1 +/- 0.5 and 1.5 +/- 0.8 mM respectively). Control studies with MRC-5 cells indicate appreciable selectivity towards the cancer cells targeted. Significant (p < 0.005) growth inhibition and cytotoxicity effects for the thiazoles 3 were corroborated by cell count and clonogenic assays using the same cancer cell lines at 5 and 10 mM agent concentrations. Cell cycle, caspase activation and Western blot assays demonstrated that compounds 3b ' and 3f induce cancer cell death via caspase-dependent apoptosis. The combination of straight forward synthesis and high activity makes the thiazoles 3 an interesting lead for further development.