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.
Medicinal Chemistry
Title:Synthesis and Immunosuppressive Activity of New Mycophenolic Acid Derivatives
Volume: 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
Affiliation:
Keywords: Immunossupression, mycophenolic acid, thalidomide, mixed lymphocyte reaction assay, immunossupressive drugs.
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.Export Options
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Cite this article as:
Barbieri P. Karina, Ercolin dos R. Lucas, Louat Thierry, Polesi C. Marisa, Chin M. Chung, Zeppone C. Iracilda and Santos L. dos Jean, Synthesis and Immunosuppressive Activity of New Mycophenolic Acid Derivatives, Medicinal Chemistry 2017; 13 (2) . https://dx.doi.org/10.2174/1573406412666161207121226
DOI https://dx.doi.org/10.2174/1573406412666161207121226 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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