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.
Subject(s)
Immunosuppressive Agents/chemical synthesis , Prodigiosin/analogs & derivatives , Pyrroles/chemical synthesis , Animals , Cell Survival/drug effects , Female , Humans , Hypersensitivity, Delayed/drug therapy , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/toxicity , In Vitro Techniques , Lymphocytes/cytology , Lymphocytes/drug effects , Mice , Mice, Inbred C57BL , Prodigiosin/chemical synthesis , Prodigiosin/chemistry , Prodigiosin/pharmacology , Prodigiosin/toxicity , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrroles/toxicity , Spleen/cytology , Spleen/drug effects , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A series of condensed N-aryl-2-cyano-3-oxo-3-pyrazolyl-propanamides were synthesized and evaluated for immunomodulating activity following intraperitoneal administration. These new molecules were found to enhance macrophage cytotoxicity and stimulate host mediated antibacterial defences in mice. The compound 3-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol- 3-yl]-3-oxo-N-phenyl-propanamide, chosen for wider pharmacological investigation, proved effective in preventing adjuvant-induced arthritis development in rats.
