Mechanism of thymidylate synthase inhibition by N4-hydroxy-(N4-hydroxy-5- fluoro)-dCMP in view of the structure and conformation of N4-hydroxy-(N4-hydroxy-5-fluoro)-cytosine calculated by the AB initio quantum mechanical methods.

Abstract

Thymidylate synthase (EC 2.1.1.45) slow-binding inhibition by N4-hydroxy-dCMP (oh4dCMP) was shown to depend on conformation of the exocyclic N4-OH group, with the anti rotamer, relative to the ring N(3), indicated as an active species. 1 Potentiation of inhibition by the 5-fluoro substituent, observed for N4-hydroxy-5-fluoro-dCMP (oh4f5CMP), was explained in terms of hydrogen bonding between the N4-OH and C(5)-F groups, influencing an assumed syn-anti equilibrium by stabilization of the anti rotamer.1 In order to test the latter hypothesis two cytosine analogues, N4-hydroxy-cytosine (oh4C) and N4-hydroxy-5-fluorocytosine (oh4f5C), were theoretically studied, and their molecular structures determined, by ab initio quantum mechanical methods.KeywordsTautomeric FormSelf Consistent FieldTransition State StructureBond SaturationSelf Consistent Field MethodThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.