Open AccessDesign and Catalyzed Activation of Mycophenolic Acid Prodrugs
Author(s) -
Michael A. Plunk,
Jeremy M. Quintana,
Carly M. Darden,
Michael C. Lawrence,
Bashoo Naziruddin,
Robert R. Kane
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00079
Subject(s) - mycophenolic acid , prodrug , pharmacology , catalysis , combinatorial chemistry , chemistry , computer science , medicine , biochemistry , transplantation
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 Pd 0 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.