MOLECULAR MECHANISM OF THYMIDYLATE SYNTHASE-CATALYZED REACTION AND INTERACTION OF THE ENZYME WITH 2-SUBSTITUTED AND OR 4-SUBSTITUTED ANALOGS OF DUMP AND 5-FLUORO-DUMP/

Thymidylate synthase is a target enzyme in anticancer, antiviral, anti fungal and antiprotozoan chemotherapy. With two dUMP analogues, 5-fluo ro-dUMP (FdUMP) and 5-(trifluoromethyl)-dUMP (CF(3)dUMP), strong thymi dylate synthase inhibitors and active forms of drugs, the inhibition m echanism is based on the reaction mechanism. Recent comparative studie s of new dUMP analogues, containing more than one substituent in the p yrimidine ring, showed that substitution of the pyrimidine ring C-(4)= O group in FdUMP by either C-(4)=N-OH group (in N-4-hydroxy-FdCMP) or C-(4)=S group (in 4-thio-FdUMP) preserves high inhibitory potency of t he drug but may alter its specificity for thymidylate synthases from v arious sources, which differ in sensitivity to slow-binding inhibition by FdUMP. Informations suggesting mechanisms responsible for the fore going have been reviewed, including results of molecular modeling stud ies suggesting interaction of the pyrimidine C-(4)=O group, or ist mod ification, with the N-5,N-10-methylene (sic).