Synthesis and Immunosuppressive Activity of Novel Prodigiosin Derivatives

Abstract

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 gamma-chain, which is exclusive of all IL-2 cytokine family receptors. Blocking common gamma-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.

The Serratia gene cluster encoding biosynthesis of the red antibiotic, prodigiosin, shows species- and strain-dependent genome context variation

“…Consequently, prodigiosins are of interest because they might have potential clinical utility. Prodigiosins and synthetic derivatives have been shown to have potent and specific immunosuppressive activity, with novel targets clearly distinct from other drugs (D'Alessio et al, 2000;Mortellaro et al, 1999;Tsuji et al, 1990Tsuji et al, , 1992. Montaner et al (2000) showed that prodigiosin extracted from S. marcescens could induce apoptosis in haematopoietic cancer cell lines including acute T-cell leukaemia, myeloma and Burkitt's lymphoma, with little effect on non-malignant cell lines.…”

Apoptosis-Mediated Cytotoxicity of Prodigiosin-Like Red Pigment Produced by .GAMMA.-Proteobacterium and Its Multiple Bioactivities

“…31) In addition, replacement of the A-pyrrole ring with a thiophene group on synthetic prodigiosin molecule results in disappearance of the ability to promote strand-scission of supercoiled DNA in the presence of copper 32) and cytotoxicity. 33) The same effect is also achieved by attaching an electron-withdrawing substituent (acetyl group) to the 5Ј-position of the A-pyrrole ring. 25) Therefore, PG-L-1 molecule might have different structure from PG molecule at A-pyrrole ring.…”

Synthesis of 3-hydroxy-2H-iminolactones and 3-hydroxy-2H-pyrrol-2-ones from reaction between isocyanides and methyl-2-acetylacetoacetate

“…[8][9][10] Cycloadditon reactions of this type are unique to isocyanides. The reaction of isocyanides with carbon-carbon double bonds tends to occur in a stepwise manner and is involves a zwitterionic intermediate the ultimate fate of which appears to be dictated by the nature of the original double bond substrate.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] Using the isocyanide carbon atom for synthesis of many cyclic systems in a formal…”