Synthesis and Characterization of an Anti-Apoptotic Immunosuppressive Compound for Improving the Outcome of Islet Transplantation
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- 作者：Hao Wu ; Jayaprakash Pagadala ; Charles Ryan Yates ; DuaneD. Miller ; Ram I. Mahato
- 刊名：Bioconjugate Chemistry
- 出版年：2013
- 出版时间：December 18, 2013
- 年：2013
- 卷：24
- 期：12
- 页码：2036-2044
- 全文大小：430K
- 年卷期：v.24,no.12(December 18, 2013)
- ISSN：1520-4812
文摘
Mycophenolic acid (MPA) is a commonly used immunosuppressive drug for human islet transplantation. However, it is toxic to transplanted islets, causing primary nonfunction. We recently synthesized a quinic acid derivative, 1,3,4,5-tetrahydroxy-N-propylcyclohexanecarboxamide (KZ41), which has anti-inflammatory and anti-apoptotic effects. We hypothesized that the conjugate (E)-2,3,5-trihydroxy-5-(propylcarbamoyl) cyclohexyl 6-(4-ethoxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (JP-3-110), which is composed of KZ41 and MPA through esterification, can suppress the immune rejection while inducing less toxicity. Early characterization showed that the solubility of JP-3-110 was significantly higher than that of MPA, though JP-3-110 was still poorly water-soluble. The ester bond connecting KZ41 and MPA is stable for a limited duration (<4 weeks). Pharmacological studies demonstrated that JP-3-110 induced significantly less activated caspase 3 and apoptotic cell death of human islets than MPA, while maintaining an equally potent immunosuppressive effect. A similar immunosuppressive effect of JP-3-110 and MPA in humanized NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NOD scid gamma, NSG) mice with adoptively transferred human immunity was observed. Taken together, our results demonstrated that JP-3-110 can be a safer immunosuppressive agent for human islet transplantation.