title: Synthesis and Immunosuppressive Activity of New Mycophenolic Acid Derivatives.
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.
  
  
  CONCLUSIONS
  All these data have shown that compound 3d is a promising lead compound useful in the immunosuppressive therapy.
authors.forename: Karina P
authors.initials: KP
authors.lastname: Barbieri
authors.forename: Lucas Dos R
authors.initials: LDR
authors.lastname: Ercolin
authors.forename: Thierry
authors.initials: T
authors.lastname: Louat
authors.forename: Marisa C
authors.initials: MC
authors.lastname: Polesi
authors.forename: Chung M
authors.initials: CM
authors.lastname: Chin
authors.forename: Iracilda C
authors.initials: IC
authors.lastname: Zeppone
authors.affiliation: School of Pharmaceutical Science, State University of São Paulo (UNESP), P.O. Box: 14801-902, Araraquara, São Paulo, Brazil.
authors.forename: Jean L Dos
authors.initials: JLD
authors.lastname: Santos
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D053583:Interleukin-1beta / Q000378:metabolism; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D009173:Mycophenolic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D013792:Thalidomide / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013792:Thalidomide; D009173:Mycophenolic Acid
keywords: Immunossupression; immunossupressive drugs; mixed lymphocyte reaction assay; mycophenolic acid; thalidomide