Synthesis and immunosuppressive activity of novel prodigiosin derivatives.
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.
D'Alessio
R
R
Departments of Chemistry and Pharmacology, Discovery Research Oncology, Pharmacia & Upjohn SpA, Nerviano (MI), Italy. roberto.dalessio@eu.pnu.com
Bargiotti
A
A
Carlini
O
O
Colotta
F
F
Ferrari
M
M
Gnocchi
P
P
Isetta
A
A
Mongelli
N
N
Motta
P
P
Rossi
A
A
Rossi
M
M
Tibolla
M
M
Vanotti
E
E
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C119625:4-benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2'-bi-1H-pyrrole; D007166:Immunosuppressive Agents; D011758:Pyrroles; D011353:Prodigiosin