The use of quantum chemical indices in the interpretation of biological activity of some substituted uracils

Abstract

Calculations are performed on a series of 40 uracils substituted in positions 1, 5 and 6 using a semiempirical molecular orbital (MO) method with complete neglect of differential overlap (CNDO/2). These compounds are potent inhibitors of uridine phosphorlyase from 256 rat tumours. Approximate ground state electronic properties are obtained for each molecule studied as well as the electrostatic potential. First- and second-order interaction energies for 14 hypothetical point charges around the drug molecule are calculated. These points provide some information on the molecule as seen by either another molecule or by a surface Relationships between reported antitumour activity expressed as p( C 50), the negative logarithm or the molar concentration required to achieve 50% inhibition of enzyme activity, and the calculated chemical indices are formulated by performing multiple regression analyses. The best correlations obtained between the biological activity p( C 50) and the electronic indices are considered in a mechanistic context. These equations can be used to predict the activity of untested molecules.