title: Synthesis and characterization of an anti-apoptotic immunosuppressive compound for improving the outcome of islet transplantation.
abstract: 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-Prkdc(scid)Il2rg(tm1Wjl)/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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center , Memphis, Tennessee, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Pagadala
authors.forename: Charles Ryan
authors.initials: CR
authors.lastname: Yates
authors.forename: Duaned
authors.initials: D
authors.lastname: Miller
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: C000589734:2,3,5-trihydroxy-5-(propylcarbamoyl)cyclohexyl 6-(4-ethoxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate; D001572:Benzofurans; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011801:Quinic Acid; D009173:Mycophenolic Acid