RESUMEN
New conjugates of mycophenolic acid (MPA) and adenosine derivatives were synthesized and assessed as potential immunosuppressants on Jurkat cell line and peripheral blood mononuclear cells (PBMC) from healthy donors. As compared to MPA, all compounds were found to be more active against Jurkat cell line. The antiproliferative activities were compared with MPA and adenosine, in both 2',3'-O-isopropylidene protected and free hydroxyl groups possessing forms. The obtained results were also discussed in terms of selectivity index, defined as SI = IC50/EC50.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/síntesis química , Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/síntesis química , Adenosina/química , Adenosina/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Células Jurkat , Ácido Micofenólico/química , Ácido Micofenólico/farmacologíaRESUMEN
BACKGROUND: Mycophenolic acid (MPA) possesses antibacterial, antifungal, antiviral, immunosuppressive and anticancer properties. It is a non-competitive and reversible inhibitor of dehydrogenase inosine-5'-monophosphate (IMPDH). This compound belongs to the immunosuppressive drugs used for the prevention of both acute and chronic transplant rejection. Until now, two derivatives of MPA have been used clinically: mycophenolate mofetil (MMF, CellCept) and mycophenolate sodium (MPS, Myfortic). They cause, similar to MPA, although at lower degree, the side effects such as vomiting, abdominal pain, diarrhea, nausea, gastrointestinal, urogenital tract, blood or nervous system disorders. These drawbacks and glucuronidation of MPA in vivo limit the use of these compounds as pharmaceuticals. Therefore, research is still going on for more effective analogs that are less toxic to the organism and could improve the quality of life of patients. CONCLUSION: In this review article, the authors present the synthesis of novel derivatives of mycophenolic acid, together with their initial biological investigations.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Ácido Micofenólico/uso terapéutico , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/química , Estructura Molecular , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/químicaRESUMEN
The new conjugates of mycophenolic acid (MPA) were obtained in the reaction of N(6)-(ω-aminoalkyl)adenosines with MPA in the presence of EDCI as a coupling reagent. New compounds 4a-h were evaluated on leukemia cell line (Jurkat) and PBMC from healthy donors. Length of the linker influenced observed activity. The compound 4b possessing 1,3-diamine spacer exhibited the most promising results and can be considered to further investigations.
Asunto(s)
Adenosina/síntesis química , Antineoplásicos , Ácido Micofenólico/química , Adenosina/análogos & derivados , Adenosina/química , Adenosina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Leucocitos Mononucleares , Estructura MolecularRESUMEN
Inosine 5'-monophosphate dehydrogenase (IMPDH) is important molecular target for potential anticancer, antiviral, antibacterial and immunosuppressive agents. A lot of compounds were obtained to establish their activity toward this enzyme, and to improve therapeutic properties of IMPDH inhibitors used as the drugs. Some of the recently reported analogs exhibited promising results during in vitro and in vivo examinations in comparison to substances applied in clinic. In this review, we describe synthesis and biological activity evaluations of the newly designed IMPDH inhibitors.