Synthesis and Modifications of Phosphinic Dipeptide Analogues

Abstract

Pseudopeptides containing the phosphinate moiety (-P(O)(OH)CH2-) have been studied extensively, mainly as transition state analogue inhibitors of metalloproteases. The key synthetic aspect of their chemistry is construction of phosphinic dipeptide derivatives bearing appropriate side-chain substituents. Typically, this synthesis involves a multistep preparation of two individual building blocks, which are combined in the final step. As this methodology does not allow simple variation of the side-chain structure, many efforts have been dedicated to the development of alternative approaches. Recent achievements in this field are summarized in this review. Improved methods for the formation of the phosphinic peptide backbone, including stereoselective and multicomponent reactions, are presented. Parallel modifications leading to the structurally diversified substituents are also described. Finally, selected examples of the biomedical applications of the title compounds are given.

The Role of the Phosphorus Atom in Drug Design

“…The use of phosphonates and phosphinates as inhibitors of C:N ligases by mimicking the transition state of the product of these enzymes at the active site has been reported . For example, compound 156 is a noncompetitive inhibitor of glutathionylspermidine synthase (GspS) from Crithidia fasciculata .…”

“…The use of phosphonates and phosphinates as inhibitors of C:Nl igasesb ym imicking the transition state of the product of these enzymes at the active site has been reported. [134][135][136] For example, compound 156 is an oncompetitive inhibitor of glutathionylspermidine synthase (GspS) [137] from Crithidia fasciculata. More excitingly,acompound structurally related to 156 coupled with spermidine gave rise to slow,t ight-binding inhibitors of GspS from Escherichia coli.…”

A Quick and Clean Procedure for Synthesis of α‐Aminophosphonates in Aqueous Media

“…Recently, several procedures have been reported for the synthesis of α-aminophosphonates under solvent and catalyst free conditions with excellent yield, or using easily available catalysts; moreover, these procedures seems to be extremely simple [27][28][29][30][31][32][33]. In continuation with our investigation on the synthesis of α-aminophosphonates [34][35][36][37][38][39][40][41][42], herein we report a green and mild protocol for the synthesis of α-aminophosphonates in aqueous media without a catalyst (Scheme 1).…”

Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

“…A number of excellent reviews on various aspects of their activity in natural systems have been published [16,17]. In view of the broad biological applications of the optically active α-amino-C-phosphinic acids and their peptidic derivatives, in the last years the development of suitable synthetic methodologies for their preparation in optically pure form has been a topic of great interest in several research groups [31,32]. In this context, now we would like to report herein a summary of the stereoselective synthesis of α-amino-C-phosphinic acids and their derivatives covering the last 20 years.…”