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Synthesis and Immunosuppressive Activity of Novel Prodigiosin Derivatives

2000; American Chemical Society; Volume: 43; Issue: 13 Linguagem: Inglês

10.1021/jm001003p

1520-4804

Roberto D’Alessio, Alberto Bargiotti, Orlando Carlini, Francesco Colotta, Mario Ferrari, Paola Gnocchi, Annamaria Isetta, Nicola Mongelli, Pietro M. Motta, Arsenia Rossi, Mario Rossi, Marcello Tibolla, Ermes Vanotti,

Natural product bioactivities and synthesis

Prodigiosins (Ps) represent a family of naturally occurring red pigments characterized by a common pyrrolylpyrromethene skeleton. Some members of this family have been shown to possess interesting immunosuppressive properties exerted with a novel mechanism of action, different from that of currently used drugs. In fact, Ps inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with a cell surface receptor component called common γ-chain, which is exclusive of all IL-2 cytokine family receptors. Blocking common γ-chain transduction activity results in a potent and specific immunosuppressive activity. With respect to the interesting and unexploited immunomodulating properties of this family of compounds we initiated a medicinal chemistry program aimed at finding novel prodigiosin derivatives with improved immunosuppressive activity and lower toxicity. Utilizing an unprecedented and flexible way of assembling the prodigiosin frame, a number of new derivatives have been prepared and tested leading to the choice of 4-benzyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-1H-pyrrole (PNU-156804, 16) as a lead immunosuppressant.