| Abstract
| - An ab initio quantum mechanics calculation is reported which predicts the orientation ofindenoisoquinoline 4 in the ternary cleavage complex formed from DNA and topoisomerase I(top1). The results of this calculation are consistent with the hypothetical structures previouslyproposed for the indenoisoquinoline−DNA−top1 ternary complexes based on molecularmodeling, the crystal structure of a recently reported ternary complex, and the biological resultsobtained with a pair of diaminoalkyl-substituted indenoisoquinoline enantiomers. The resultsof these studies indicate that the π−π stacking interactions between the indenoisoquinolinesand the neighboring DNA base pairs play a major role in determining binding orientation.The calculation of the electrostatic potential surface maps of the indenoisoquinolines and theadjacent DNA base pairs shows electrostatic complementarity in the observed bindingorientation, leading to the conclusion that electrostatic attraction between the intercalatorsand the base pairs in the cleavage complex plays a major stabilizing role. On the other hand,the calculation of LUMO and HOMO energies of indenoisoquinoline 13b and neighboring DNAbase pairs in conjunction with NBO analysis indicates that charge transfer complex formationplays a relatively minor role in stabilizing the ternary complexes derived from indenoisoquinolines, DNA, and top1. The results of these studies are important in understanding the existingstructure−activity relationships for the indenoisoquinolines as top1 inhibitors and as anticanceragents, and they will be important in the future design of indenoisoquinoline-based top1inhibitors.
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