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

  • ACS Med Chem Lett. 2025 Dec 23;17(1):48-53. doi: 10.1021/acsmedchemlett.5c00681.
Anna A Griadunova  1 ,  Nicholas L Petrone  2 ,  Madeleine S Maker  1 ,  Brian Pallares  3 ,  Trevor Leung  1 ,  Allison N Shim  1 ,  Ömer H Yilmaz  4  5 ,  Jacob M Goldberg  3 ,  Jonathan Braverman  1 ,  Fang Wang  2
Affiliations
  • 1. Innovative Genomics Institute, University of California, Berkeley, Berkeley, California 94720, United States.
  • 2. Department of Chemistry, University of Rhode Island, Kingston, Rhode Island 02881, United States.
  • 3. Department of Chemistry, Colgate University, Hamilton, New York 13346, United States.
  • 4. Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
  • 5. Department of Pathology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02215, United States.
PMID: 41531982 DOI: 10.1021/acsmedchemlett.5c00681
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 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.

Keywords
ABC transporters; P-glycoprotein; anthracyclines; anticancer; doxorubicin; drug efflux; multidrug resistance.
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