The specific aims of this program are to study the interaction of the antitumor antibiotics, including quinocarcin, tetrazomine, the bioxalomycins and ecteinascidin 743 with cellular nucleic acids. The DNA-alkylating capacity of these drugs compared with their ability to cause oxidative damage to nucleic acids will be explored. The synthesis of members of this class of antitumor drugs will continue to be developed with the objective of harnessing the synthetic methodology developed to make new, less toxic, more selective and more potent antitumor drugs. In addition, the tools of synthesis will be exploited to synthesize mechanistic probes for the interaction of these substances with cellular nucleic acids and proteins that bind to cellular nucleic acids. We have recently discovered that bioxalomycin alpha2 specifically cross-links duplex DNA at 5'CG3' steps. We propose to elucidate the exact molecular structure of the covalent adduct. This finding has inspired new design concepts for simpler analogs based on the quinocarcin/bioxalomycin/Et 743 core that may be capable of cross-linking DNA. Coupled to these studies, we propose to examine the cross-linking of DNA to DNA-binding proteins by bioxalomycin, Et 743 and several synthetic hybrids; the proteins of interest are the High Mobility Group (HMG) nonhistone chromosomal proteins that associate with DNA in the minor groove.
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