Synthesis and Characterization of a Novel Mycophenolic
Acid–Quinic Acid Conjugate Serving as Immunosuppressant with
Decreased Toxicity
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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, <i>N</i>-[2-[[(4<i>E</i>)-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