This project aims at the design of new alkylating agents that would be optimized for selectivity of reaction with particular locations in a DNA sequence. A premise of this work is the possibility that the antitumor effectiveness of alkylating agents depends on their reaction with certain, as yet undetermined, sites in the genome, and that their reaction at other sites would only yield deleterious effects. The approach is to search for and achieve a structural understanding of DNA sequence selective reactions by antitumor alkylating agents. Our previous work had shown that DNA sequence selective reactions do exist for nitrogen mustards and that the nature of the selectivity can be altered by altering the structure of the nitrogen mustard. In current work, the sequence selectivities have been quantitated and analysed by computer, and plausible hypotheses have been generated of the structural bases of the selectivities. It was found that the sequence selectivity pattern of most nitrogen mustards could be explained in large part as arising from the effects of neighboring base pairs on the molecular electrostatic potential in the vicinity of the reactive guanine-N7 positions. Striking deviations from this general pattern were observed for uracil mustard and for quinacrine mustards. The unique selectivities of these two mustards was explained on the basis of structural hypotheses generated with the aid of molecular modelling using computer graphics and space-filling models. It is planned to test these hypotheses by the design and synthesis of compounds that would be predicted to have enhanced or altered sequence selectivities. A later stage of this project will examine DNA sequence selectivities in chromatin and in intact cells.
