O-phosphotyrosine analogues: Synthesis and therapeutic role in modulation of signal transduction

Abstract

The development of O-phosphotyrosine (pTyr) analogues is reviewed, along with their application in peptidomimetic ligands to proteins implicated in disease-states arising from dysfunctional intracellular signal transduction pathways. Salient features of chemical syntheses are critiqued, including those of established mimetics such as 4'-(phosphonomethyl)phenylalanine (Pmp), 4'- (phosphono)phenylalanine (Ppp) and 4'-(phosphonodifluoromethyl)phenylalanine (F2Pmp), their respective (α-methyl)phenylalanine analogues and “preorganised” side-chain cyclised pTyr mimetics. Syntheses of 4'-(phosphinomethyl)phenylalanines are also described, as are “bone-directing” residues such as 4'-(diphosphonomethyl)phenylalanine (dpmF), 3',4'-(diphosphono)phenylalanine and 4'- carboxymethyloxy-3'-(phosphono)phenylalanine (CPP), capable of eliciting additional interactions with pTyr-binding subsites of specified proteins. The utility of [(4'-phosphonomethyl)phenyl]propenoic acid in current developments is also discussed as a route to a range of α- and β-substituted pTyr mimetics, and to pTyr mimetics bearing the requisite β-vinyl functionality to facilitate macrocyclisation via olefin metathesis - of interest in the development of structures exhibiting global conformational constraint. Finally, developments in prodrug presentation of pTyr mimetics are also discussed.