No abstract

The established cytotoxic agent RITA contains a thiophene-furan-thiophene backbone and two terminal alcohol groups. Herein we investigate the effect of using thiazoles as the backbone in RITA-like molecules and modifying the terminal groups of these trithiazoles, thereby generating 41 unique structures. Incorporating side chains with varied steric bulk allowed us to investigate how size and a stereocenter impacted biological activity. Subjecting compounds to growth inhibition assays on HCT-116 cells showed that the most potent compounds ,, and had GI values of 4.4, 4.4, and 3.4 μM, respectively, versus RITA (GI of 800 nM). Analysis of these compounds in apoptosis assays proved that ,, and were as effective as RITA at inducing apoptosis. Evaluating the impact of on proteins targeted by RITA (p53, c-Myc, and Mcl-1) indicated that it acts via a different mechanism of action to that of RITA. RITA suppressed Mcl-1 protein via p53, whereas compound suppressed Mcl-1 expression via an alternative mechanism independent of p53.