(Principal Investigator's) The proposed research project involves the synthesis and evaluation of new antitumor agents capable of inhibiting topoisomerase II and cleaving DNA. Although many clinically used antitumor agents target topoisomerase II and cleave DNA, the compounds from this laboratory act by novel mechanisms, which translates to a unique spectrum of antitumor activity. Currently, there are 14 compounds from this laboratory undergoing in vivo evaluation at the National Cancer Institute. The current proposal presents new designs based on the compounds currently under study. Th topoisomerase II-DNA crosslinkers are designed to link the DNA to the enzyme thereby causing irreversible damage. The iminoquinone-based topoisomerase II inhibitors are based on the pyrrolo(1,2-a)benzimidazole-based antitumor agents discovered in this laboratory and the pyrroloiminoquinone natural products. These inhibitors are designed to intercalate DNA and then alkylate the tyrosin residue important in topoisomerase II activity. In vivo results indicate that inhibitors of this type possess activity, particularly against melanoma and ovarian cancers. Finally, DNA cleaving agents acting at the phosphate backbone reductively alkylate the phosphate backbone at specific base pairs followed by hydrolytic cleavage of the resulting phosphate triester. This new class of DNA cleaving agent is known to possess antitumor activity and may also be convenient reagents for DNA chemical cleavage. This proposal presents new and improved DNA cleaving agents of this class.
