Design and Catalyzed Activation of Mycophenolic Acid Prodrugs
Design and Catalyzed Activation of Mycophenolic Acid Prodrugs
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DOI：
10.1021/acsmedchemlett.1c00079
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发表时间：
2021-04-08
影响因子：
4.2
通讯作者：
Kane, Robert R.
中科院分区：
文献类型：
--
作者：
Plunk, Michael A.;Quintana, Jeremy M.;Kane, Robert R.
霉酚酸（MPA）及其吗啉代酯前体药物霉酚酸酯（MMF）广泛应用于实体器官移植。这些药物由于其对肌苷-5 '-单磷酸脱氢酶（IMPDH）的有效抑制而防止排斥，IMPDH是一种对淋巴细胞增殖至关重要的酶。作为在细胞移植中提供局部免疫抑制的策略，合成并表征了四种霉酚酸前药，其设计为通过两种不同的机制释放MPA。一个硝基苄基醚前药有效地转化为MPA后，暴露于细菌硝基还原酶，而炔丙基醚转化为活性药物的固定化钯度纳米粒子。在体外，这两种前药对IMPDH都没有活性，并且相对于活性药物表现出较低的毒性，这表明它们具有提供局部免疫抑制的潜力。
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 degrees 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.