Design, synthesis, and biological evaluation of novel thiazole-based CYP1B1 inhibitors to overcome paclitaxel resistance.

Abstract

Cytochrome P450 1B1 (CYP1B1) is a drug-metabolizing enzyme that is overexpressed in a variety of malignant tumors. Therefore, CYP1B1 has emerged as an important therapeutic target for cancer treatment and the management of drug resistance. In this study, we employed the pharmacophore fusion strategy to optimize the structure of two potent CYP1B1 inhibitors previously identified by our group, compound VII (an N-aryl-2,4-bithiazole-2-amine derivative) and compound VIII (a monothiazole-benzamide derivative), thus designing and synthesizing a new series of derivatives. Through systematic biological evaluation, a variety of highly active and selective CYP1B1 inhibitors were identified. Among these compounds, 12 was identified as the most promising preferred compound, which not only shows strong CYP1B1 inhibitory activity, but also has high selectivity for CYP1B1 compared with other major CYP isoforms. Biological evaluation demonstrated that 12 restored the sensitivity of A549/Taxol-resistant cells to paclitaxel treatment again, while maintaining good selectivity for normal cells and inhibiting colony formation and cell migration. Pharmacokinetic studies demonstrated that 12 showed favorable metabolic stability in human liver microsomes and achieved a moderate systemic exposure following intravenous administration in rats. Collectively, these findings supported 12 as a promising CYP1B1 inhibitor capable of overcoming paclitaxel resistance.

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