Design and Synthesis of Novel pH-Sensitive Anticancer Drug and Efflux Pump Inhibitor Conjugates

Abstract

Resistance to anti-cancer therapies has proven a challenge for effective treatments. Efflux pumps when overexpressed in cancer cells, eject drugs from the cell, rendering them ineffective. The pH of cancer cells is generally lower than that of normal cells, due to their raised metabolic rate. This disparity can be exploited using a prodrug that is activated at an acidic pH, resulting in improved efficacy for treatments. Co-administration of an efflux pump inhibitor (EPI) with an anticancer drug can prevent drug efflux, reduce normal cell cytotoxicity, and improve the efficacy. Using the cytotoxic drug, doxorubicin, the EPIs, MC70 and norverapamil with the cis¬-aconityl linker, possible conjugates were modelled. We chose the cis-aconityl linker because it is acid-labile at pH values <7 and, is suitable for targeted release of doxorubicin in tumours. Linker conjugates for glucosamine and 4-aminotetrahydropyran, model compounds for doxorubicin, 4-phenylphenol, the model compound for MC70, and dibutylamine, phenethylamine and N-methyl-phenethylamine, model compounds for norverapamil, were synthesized and analysed. This study has laid the groundwork for a novel way of increasing the efficacy of doxorubicin, and possibly other medicine, which will hopefully lead to more studies and eventual treatments and therapies.