Selective Inhibition of the ABCG2 Transporter by Primaquine Derivatives Reverses the Multidrug Resistance of Tumor Cells.

Multidrug resistance (MDR) poses a significant challenge in cancer therapy, often leading to treatment failure and relapse. ATP-binding cassette (ABC) transporters, particularly ABCG2, play a pivotal role in MDR development by actively expelling chemotherapeutic agents from cancer cells. This study investigates the effects of two groups of primaquine derivatives-fumardiamides (-) and -ureas (, ), both bearing halogenated benzene rings-on the activity of P-glycoprotein (P-gp) and ABCG2. Their potential to reverse MDR was evaluated through a series of functional assays aimed at comparing transporter-compound interactions. The results indicated that fumardiamide derivatives, specifically , , and , exhibited potent inhibition of ABCG2 while having no effect on P-gp, demonstrating a selective mode of action. The tested derivatives displayed low to moderate cytotoxicity and did not affect ABCG2 expression or localization. Moreover, these compounds enhanced the sensitivity of drug-resistant cancer cell lines to mitoxantrone, underscoring their potential to overcome ABCG2-mediated MDR. These findings suggest that chemical modifications of primaquine, particularly the incorporation of fumardiamide moieties, confer novel biological properties, providing promising leads for the development of selective ABCG2 inhibitors.