Relationships between nucleotide incorporation rates and molecular parameters obtained by molecular modelling and chromatography

Abstract

Deoxyuridine derivatives play an important role in pharmaceutical chemistry as they are potential antiviral and antitumour agents. Their pharmacological activity depends on their ability to incorporate into DNA in their triphosphate forms. High-performance liquid chromatographic (HPLC) retention behaviour of a series of 5-alkyl, alkenyl and alkynyl substituted deoxyuridine derivatives were investigated on reversed-phase stationary phase using various mixtures of methanol and water as mobile phases. The slope and the intercept values of the linear relationships between the logarithmic capacity ratio (log k') values and methanol concentration have been calculated. Non-polar, non-polar unsaturated and polar surface areas, surface energies, dipole moments, van der Waals radii of the derivatives have been calculated on the bases of molecular mechanics by PC Model approach. The correlation study of the above-mentioned parameters revealed that hydrophobic and hydrophilic surface areas and the electronic effects of the substituents determine not only the retention behaviour of the derivatives but also their incorporation rate into DNA in their triphosphate forms.