O-Phosphotyrosine Analogues: Synthesis and Therapeutic Role in Modulation of Signal Transduction

Author(s): Nick J. Wardle, Harry R. Hudson, S. W. Annie Bligh.

Journal Name: Current Organic Chemistry

Volume 14 , Issue 5 , 2010

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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.

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Article Details

VOLUME: 14
ISSUE: 5
Year: 2010
Page: [426 - 446]
Pages: 21
DOI: 10.2174/138527210790601189
Price: $58

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