Design and Catalyzed Activation of Mycophenolic Acid Prodrugs

ACS Med Chem Lett. 2021 Apr 8;12(5):812-816. doi: 10.1021/acsmedchemlett.1c00079.

Michael A Plunk ¹, Jeremy M Quintana ¹, Carly M Darden ², Michael C Lawrence ² ³, Bashoo Naziruddin ² ⁴, Robert R Kane ¹ ²

Affiliations

1 Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76706, United States.
2 Institute of Biomedical Studies, Baylor University, Waco, Texas 76706, United States.
3 Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, Texas 75204, United States.
4 Baylor Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas 75204, United States.

PMID: 34055230 DOI: 10.1021/acsmedchemlett.1c00079

Abstract

Mycophenolic acid (MPA) and its morpholino ester prodrug mycophenolate mofetil (MMF) are widely used in solid organ transplantation. These drugs prevent rejection due to their potent inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH), an enzyme vital for lymphocyte proliferation. As a strategy to provide localized immunosuppression in cell transplantation, four mycophenolic acid prodrugs designed to release MPA by two distinct mechanisms were synthesized and characterized. A nitrobenzyl ether prodrug was effectively converted to MPA upon exposure to Bacterial nitroreductase, while a propargyl ether was converted to the active drug by immobilized Pd⁰ nanoparticles. In vitro, both prodrugs were inactive against IMPDH and exhibited reduced toxicity relative to the active drug, suggesting their potential for providing localized immunosuppression.

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