Improving Anticancer Activity of Doxorubicin by 4′- <i>epi</i> -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 <i>epi</i>-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.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-12-23
DOI
https://doi.org/10.1021/acsmedchemlett.5c00681
Primary Topic
Drug Transport and Resistance Mechanisms
Type
article
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article

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

Jonathan Braverman, Jacob M. Goldberg, Madeleine Maker, Brian Pallares et al.
ACS Medicinal Chemistry Letters
Drug Transport and Resistance Mechanisms
article

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

Jonathan Braverman, Jacob M. Goldberg, Madeleine Maker, Brian Pallares, Anna A. Griadunova, Nicholas L. Petrone, Ömer H. Yilmaz, Allison N. Shim, Fang Wang, Trevor Leung
article en

Abstract

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 <i>epi</i>-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.

ACS Medicinal Chemistry LettersVol. 17(1)
Harvard University (US), University of Rhode Island (US), Hadassah Medical Center (IL), Colgate University (US), Massachusetts General Hospital (US), Innovative Genomics Institute (US), Allen Institute (US), Koch Institute for Integrative Cancer Research At MIT (US), Massachusetts Institute of Technology (US), University of California, Berkeley (US)
Good health and well-being
Openalex Percentile: Top 31%
Drug Transport and Resistance Mechanisms
DOIOpen Access PDFOpenAlex
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Improving Anticancer Activity of Doxorubicin by 4′- <i>epi</i> -Dehydroxyamination — Jonathan Braverman, Jacob M. Goldberg, et al. · ACS Medicinal Chemistry Letters (2025) | TGRS Research Map | TGRS