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.
Highlights
Phosphinic pseudodipeptides (Figure 1) are typically defined as dipeptide analogues that replace the amide bond with the phosphinate moiety
A free amino moiety and a methyl ester form the phosphinic analogue of diketopiperazine under basic conditions [45]. Proper manipulations on these groups can be quite demanding. Achievement in this field is adequately illustrated by preparation of phosphinic dipeptides for solid-phase peptide synthesis
Application of phosphinic dipeptides as building blocks for peptide synthesis on a solid phase demanded the development of a convenient orthogonal protective group for the phosphinic moiety
Summary
Phosphinic pseudodipeptides (Figure 1) are typically defined as dipeptide analogues that replace the amide bond with the phosphinate moiety. In the early period of these studies (during the 80s of the 20th century), phosphonamidate and phosphonate pseudopeptides attracted major attention These pseudopeptides emerged as invaluable tools in fundamental structural and mechanistic studies carried out on prototypical metalloproteases, thermolysin and carboxypeptidase A [1,8,9,10,11,12,13,14]. Certain drawbacks, such as hydrolytic instability of the P-N bond and frequent limited activity of the P-O derivatives excluded them from later practical applications. The literature data published after 2000 are discussed, and earlier papers are only selectively highlighted to give the proper background
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