QUANTITATIVE RELATIONSHIPS BETWEEN CHEMICAL STRUCTURE, CHROMATOGRAPHIC RETENTION AND BIOLOGICAL ACTIVITY

Linear free energy relationships (LFER) are employed to study the effect of molecular structure on biological activity and chromatographic retention of selected groups of substances. Hansch's extrathermodynamic approach to quantitative structure-activity relationships (QSAR) is expanded by the incorporation of multivariate statistical methods such as cluster and discriminant analyses. QSAR correlation equations were formulated for enzyme inhibition by quinazoline compounds that are considered potential anticancer drugs. For dihydrofolate reductase from both human acute lymphocytic leukemia cells and murine L1210R cells, QSAR's obtained with 50 quinazolines were similar, whereas, the inhibition of thymidylate synthetase from murine L1210S cells and from Lactobacillus casei by 33 quinazolines results in different QSAR's.;Enthalpy-entropy compensation in RPC affords a means to express the free energy change associated with the chromatographic process as a function of both the eluent composition and temperature. A method is presented to transform retention data obtained for a solute at a given temperature and solvent composition to another set of experimental conditions. This method leads to the development of a hydrophobic index system that exploits linear free energy relationships between chromatographic retention and molecular structural parameters of solute at various solvent compositions. The hydrophobic index also serves as a predictor of the elution order of the sample components on the basis of their molecular structures thus optimizes the design of chromatographic system, besides characterizes the hydrophobic properties of biological substances for use in QSAR studies and hence drug design.;Recent advances in both instrumentation and methodology of high-performance liquid chromatography (HPLC) facilitate the reliable measurement of certain physico-chemical properties rapidly and efficiently. Reversed-phase chromatography (RPC) with octadecyl-silica as the stationary phase is employed to investigate quantitative structure-retention relationships (QSRR) for quantifying certain molecular properties and predicting chromatographic retention. It is found that chromatographic retention increments measured on different octadecyl-silica columns are collinear for various substituents of catecholamine molecules, thus retention data obtained from one column can be used to calculate the magnitude of retention time in another RPC system as long as the eluent composition is the same.