Substrate spectrum of mandelate racemase - Part 2. (Hetero)-aryl-substituted mandelate derivatives and modulation of activity

Efficient enzymatic racemization of 2-hydroxy-2-heteroaryl-acetic acid deri vatives by mandelate racemase under mild conditions is reported for the fir st time. (i) Steric limitations for aryl-substituted mandelate derivatives were elucidated to be particularly striking for upsilon -substituents, wher eas m- and p-analogues were freely accepted, as well as heteroaryl- and nap hthyl-analogs. (ii) The electronic character of substituents was found to p lay an important role: whereas electron-withdrawing substituents dramatical ly enhanced the racemization rates, electron-donating analogs caused a depl etion. This effect could be ascribed to an alpha -carbanion-stabilization i n accordance with the known enzyme mechanism. The latter was modeled by com parison of gas phase deprotonation energies as a useful parameter to descri be resonance stabilization. The calculated data nicely correlate with the e xperimentally observed activities for a specific substrate as long as other parameters, such as steric restrictions, are absent or play a minor role. (C) 2001 Elsevier Science B.V. All rights reserved.