DESIGN OF COMPOSITE DRUG MOLECULES - MUTUAL EFFECTS ON BINDING TO DNAOF AN INTERCALATOR, AMSACRINE, AND A MINOR-GROOVE BINDER, NETROPSIN

A variety of spectroscopic and biochemical techniques have been employ ed to investigate the extent to which binding to DNA of an intercalato r (amsacrine or its $-carboxamide derivative SN16713) affects the bind ing of netropsin, a minor groove-targeted ligand, and vice versa. In g eneral, rather little mutual interference has been found and the bindi ng of one drug is compatible with binding of the other. The anilinoacr idines exert little or no effect on the positioning of netropsin in th e minor groove, judged by circular dichroism spectroscopy and electric linear dichroism, whereas netropsin has a perceptible effect on the i ntercalative binding of amsacrine, but not that of SN16713. Neither ac ridine drug prevents the netropsin-induced Z --> B structure reversion observed with poly(dG-dC). poly(dG-dC) in buffer containing 60% ethan ol. The kinetics of dissociation of any one drug from its DNA complex are affected little, if at all, by the simultaneous presence of the ot her. Footprinting experiments with the several drugs singly or in comb ination reveal a certain amount of mutual interference, but the select ive recognition of AT-rich sequences by netropsin tends to dominate th e recognition pattern and is largely maintained in the presence of a c onsiderable excess of amsacrine or its 4-carboxamide derivative.