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Synthesis and Immunosuppressive Activity of New Mycophenolic Acid Derivatives

[ Vol. 13 , Issue. 2 ]

Author(s):

Karina P. Barbieri, Lucas dos R. Ercolin, Thierry Louat, Marisa C. Polesi, Chung M. Chin, Iracilda C. Zeppone and Jean L. dos Santos   Pages 159 - 167 ( 9 )

Abstract:


Background: Immunosuppressive drugs are widely used to prevent and treat allograft rejection and autoimmune diseases. Mycophenolic acid (MPA) and its derivatives are currently one of the most prescribed immunosuppressive drugs; however, metabolic drawbacks and variable interand intrapatient responses limit their use.

Objective: In order to find out new safe and effective immunosuppressive compounds, we report here the synthesis and pharmacological evaluation of hybrid MPA derivatives containing the thalidomide/ phthalimide subunits.

Results: All compounds 3a-d exhibited an enhanced ability to reduce the levels of pro-inflammatory cytokines compared to the parental drugs MPA and thalidomide. The mixed lymphocyte reaction assay has demonstrated that compound 3d - (E)-(3-(1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1- yl)methyl-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enoate – has superior activity compared to that of MPA. In addition, compound 3d was less cytotoxic against Jurkat cells than MPA and did not demonstrate in vivo genotoxic effect.

Conclusion: All these data have shown that compound 3d is a promising lead compound useful in the immunosuppressive therapy.

Keywords:

Immunossupression, mycophenolic acid, thalidomide, mixed lymphocyte reaction assay, immunossupressive drugs.

Affiliation:

School of Pharmaceutical Science, State University of São Paulo (UNESP), P.O. Box: 14801-902, Araraquara, São Paulo

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