DESIGN, SYNTHESIS, DNA-SEQUENCE PREFERENTIAL ALKYLATION AND BIOLOGICAL EVALUATION OF N-MUSTARD DERIVATIVES OF DISTAMYCIN AND NETROPSIN ANALOGS

The design and synthesis of certain oligopeptides structurally related to distamycin and netropsin, but bearing mixed heterocyclic moieties capable of recognizing alternative base sites and nitrogen mustard moi eties capable of covalent binding to DNA, are described. The binding a nd thermally induced DNA cleavage, covalent interstrand cross-linking, DNA preferential alkylation and anticancer cytotoxicities of the new agents are described. In contrast to the mustard derivative derived di rectly from distamycin, the new agents give evidence of extensive DNA alkylation and interstrand cross-linking. In general, strong alkylatio n is observed at A residues for this class of agents, while the G resi dues that are alkylated appear to be more characteristic of individual compounds. Densitometric analysis of the frequency of bases adjacent to the alkylation sites (-3 to +3) revealed that the preferred bases a re exclusively A/T with little preference shown for G bases and none f or C sites. Further insight into the DNA alkylation processes afforded by the drugs was provided by an independent assay whereby heating the drug-DNA adduct with 10% aqueous piperidine only yielded strand break s specifically at G-N7 sites in the major groove.