title: Synthesis and Characterization of a Novel Mycophenolic Acid-Quinic Acid Conjugate Serving as Immunosuppressant with Decreased Toxicity.
abstract: Mycophenolic acid (MPA) is one of the most commonly used immunosuppressive drugs for improving the outcome of cell and organ transplantations. However, an undesired adverse effect of MPA impedes its application in the clinics for post-transplant patients. By conjugating MPA to quinic acid (QA) via amide bonds, we synthesized a novel immunosuppressant, N-[2-[[(4E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-1-oxo-4-hexen-1-yl]amino]ethyl]-(1α,3R,4α,5R)-1,3,4,5-tetrakis(acetyloxy)cyclohexanecarboxamide (abbreviated as MQ4), which exhibits improved stability demonstrated by its incubation in vitro with human plasma, suggesting its better resistance to hydrolytic degradation induced by plasma enzyme. While the immunosuppressive effect of MQ4 on human lymphocyte proliferation was partially compromised as shown by flow cytometry, significant decrease in cytotoxicity of MQ4 to insulin producing β cells could compensate this drawback to some degree. There was a decreased level of apoptotic mediator caspase-3, which may contribute to the decreased toxicity of MQ4 to INS-1E cells. MQ4 could further improve insulin stimulation index and downregulate NFκB expression compared to physical mixing of QA to MPA. Taken together, MQ4 is a promising immunosuppressive agent for preventing and minimizing post-transplanted immune rejection.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198-6025, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198-6025, United States.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198-6025, United States.
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D009173:Mycophenolic Acid / Q000737:chemistry* / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011801:Quinic Acid / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats
chemical_list: D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011801:Quinic Acid; D053148:Caspase 3; D009173:Mycophenolic Acid
keywords: caspase-3; immunosuppressant; mycophenolic acid; quinic acid; β cells