The ability of certain antineoplastic alkylating agents to react selectively with particular DNA sites, depending on DNA sequence and conformation, is being studied as a possible new avenue for the design of more specific drugs. The first objective is to understand at the chemical structure level the factors that govern the selectivity of DNA alkylation sites. Results so far show that the sequence selectivity of nitrogen mustards can be altered by changing the drug structure, and indicate that a structural understanding can be achieved. The second objective is to design new compounds optimized for selective reaction at certain DNA sequence sites. Synthesis and testing of the first new compounds has begun, and is being guided by computer aided molecular modelling based on specific structural hypotheses which are to be tested. The third objective is to investigate the possibility of enhancing the specificity of antitumor action. Studies have been initiated to determine the sequence selectivities in intact cells, and to determine whether there are significant hot-spots for DNA alkylation and crosslinking in the genomes of cells having different drug sensitivities.
