Synthesis of the phosphinic analogue of thyrotropin releasing hormone.
The synthesis of the phosphinic analogue of thyrotropin releasing hormone (TRH) GlpPsi[P(O)(OH)]HisProNH2, where the scissile peptide bond of TRH has been replaced by the hydrolytically stable phosphinic bond, has been achieved by a multistep synthetic strategy, providing thus one of the most potent synthetic inhibitors of pyroglutamyl peptidase II (PPII) reported to date (170 nM). The key synthetic step, an Ugi-type condensation reaction, produced directly the suitably protected for solid-phase peptide synthesis pseudodipeptidic block FmocGlu(OMe)Psi[P(O)(OH)]His(Tr)OH. Formation of the pyroglutamic ring was performed on solid phase, providing thus a general method for synthesizing pyroglutamyl phosphinic peptides on solid phase. Using this strategy, the phosphinic analogue of TRH has been synthesized for the first time.
Matziari
Magdalini
M
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece.
Bauer
Karl
K
Dive
Vincent
V
Yiotakis
Athanasios
A
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D010721:Phosphinic Acids / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D010721:Phosphinic Acids; D011480:Protease Inhibitors; D013973:Thyrotropin-Releasing Hormone; D000626:Aminopeptidases; C023166:pyroglutamyl-peptidase II; D011761:Pyrrolidonecarboxylic Acid