Design, synthesis, and biological evaluation of ocotillol derivatives fused with 2-aminothiazole via A-ring as modulators of P-glycoprotein-mediated multidrug resistance.

Overexpression of P-glycoprotein (P-gp) plays a key role in the development of multidrug resistance (MDR), the major reason for the failure of chemotherapy in clinics. Ocotillol and its derivatives had been reported with good P-gp-mediated tumor MDR reversal activity in vitro. Herein, a series of ocotillol derivatives fused with 2-aminothiazole (2-AT) via A-ring were designed and synthesized to further improve the tumor MDR reversal potency. These compounds were evaluated for their MDR reversal activity against the KBV cells by MTT assay. Among them, the most promising derivative against P-gp-mediated MDR was compound 12 with 2-AT and glycine in the A-ring. Rhodamine123 (Rh123) accumulation assay, Western blot assay, and P-gp-Glo™ assay showed that compound 12 efficiently inhibited the efflux function of P-gp by stimulating P-gp ATPase rather than downregulating its expression. Moreover, compound 12 sensitized KBV cells to paclitaxel arrested cells in the G/M phase and induced cell apoptosis. Importantly, compound 12 significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice by increasing the sensitivity of paclitaxel in vivo. Finally, the structure-activity relationships (SARs) of ocotillol derivatives were further investigated. In summary, compound 12 has the potential to overcome MDR in cancer caused by P-gp.