Design, synthesis and antitumor activity of celastrol thiazole derivatives with enhanced covalent binding capacity.

Celastrol (CEL), a natural product, has attracted great attention because of its remarkable antitumor potential. Its unique quinone methide (QM) moiety covalently binds to the thiol groups of cysteine residues, thereby exerting antitumor activity. To enhance the antitumor activity of CEL, we designed and synthesized 30 CEL thiazole derivatives with improved covalent binding capacity. Most of these derivatives exhibited enhanced anti-proliferative activity against four human cancer cell lines (MCF-7, MDA-MB-231, A549, and BGC-823) compared to CEL. Among them, compound 28 exhibited the most potent antiproliferative activity against MDA-MB-231 cells (IC50 = 0.29 ± 0.02 μM). Further pharmacological studies showed that compound 28 exhibited more extensive and stable binding to dithiothreitol (DTT, a thiol-containing model molecule) than CEL, which might account for its enhanced antiproliferative activity. Moreover, compound 28 effectively induced apoptosis in MDA-MB-231 cells and arrested cells in the G2/M phase. In conclusion, compound 28 warrants further investigation for cancer therapy.