磷酸基团在药物化学中的应用.pdfVIP

PERSPECTIVE /jmc Remarkable Potential of the r-Aminophosphonate/Phosphinate Structural Motif in Medicinal Chemistry Artur Mucha, Pawez Kafarski, and yukasz Berlicki* Department of Bioorganic Chemistry, Faculty of Chemistry, Wroczaw University of Technology, Wybrzeze_ Wyspianskiego 27, 50-370 Wroczaw, Poland ’INTRODUCTION Reactive peptidyl phosphonate diaryl esters have been suc- R-Aminophosphonic acids are broadly defined as analogues of cessfully used to covalently modify members of the serine amino acids in which the carboxylic group is replaced by a hydrolase superfamily. This approach exploits their ability to phosphonic acid or related group (usually phosphonous or phosphonylate the hydroxyl residue of the active-site serine of phosphinic acids). This results in the presence of the character- these enzymes. They act as competitive, irreversible inhibitors, istic NCP scaffold (Scheme 1). The biological activity and which, after the formation of an initial enzyme substrate com- natural occurrence of these compounds (often called R-amino- plex, bind to the active site via a transesterification reaction and phosphonates) were discovered half a century ago.1,2 Since then, thus block its catalytic function. The activity and selectivity of the interactions of inhibitors with target enzymes can be adjusted by the chemistry and biology of this class of compounds have been 3 structural optimization of the S1