Molecular modelling of DNA-antitumour drug intercalation interactions: correlation of structural and energetic features with biological properties for a series of phenylquinoline-8-carboxamide compounds.

The crystal structure of the experimental antitumour compound N-(2-dimethylaminoethyl)-2-phenylquinoline-8-carboxamide has been determined. The geometry and conformation have been used as starting points for molecular modelling of the intercalative interactions with DNA shown by the parent compound and analogues with the phenyl ring located at alternative positions on the quinoline chromophore. A molecular mechanics force field program was used for energy minimization and calculation of intermolecular (enthalphic) binding energies. The parent quinoline-8-carboxamide and derivatives with a phenyl substituent at the 4- or 5-position were judged to be poor intercalators in both structural and energetic terms. By contrast, the 2-, 3-, and 6-phenyl derivatives all had high calculated binding energies with the phenyl groups involved in stacking with DNA base pairs. The order of energies calculated for this series of compounds has been found to correlate well with both the order of experimentally derived free energies and with the in vitro cytotoxic activity.