Improving Anticancer Activity of Doxorubicin by 4'-epi-Dehydroxyamination

Efflux pump-mediated multidrug resistance is a common mechanism by which cancer cells reduce the efficacy of a broad range of small-molecule therapeutics. We discovered that substituting the 4'-hydroxy group of doxorubicina known efflux pump substratewith an epi-amino group results in a new compound, doxorubamine, which exhibits substantially improved activity against drug-sensitive and -resistant cancer cells and organoids. Mechanistic studies reveal that doxorubamine is a poor substrate of P-glycoprotein, and it thus retains high potency against multidrug-resistant cancer. This synthetic modification provides a promising strategy for circumventing multidrug resistance beyond conventional approaches that rely on efflux pump inhibition.