This proposal describes a comprehensive program involving synthetic, mechanistic, biological, and computer modeling studies directed at the elucidation of the mode of action of demonstrated and of potential cancer chemotherapeutic agents, at the rational design and development of new classes of antitumor agents, and at the development of fundamentally new methodology and strategies for the synthesis of such agents. Five projects are proposed for investigation. A major continuation study will be directed at neocarzinostatin chromophore, the recently identified, structurally unprecedented, biologically active subunit of neocarzinostatin (NCS), a drug used in human cancer chemotherapy. Efforts will focus on determining the molecular basis for the antitumor activity of NCS, on establishing the basis for its DNA cleavage selectivity, on the utilization of this information in the rational design of new antitumor agents, and on the synthesis of simplified analogues and biological probes needed in support of these studies. A second major project is focussed on dynemicin A (Dyn A), an exciting new chemotherapeutic lead exhibiting significant in vitro and in vivo antitumor activity. Attention will be directed at the mechanism of activation of Dyn A, at the rational design and development of new Dyn A analogues, at the structural basis for its DNA lesion selectivity, and at an examination of a potentially biomimetic approach to its unprecedented structure. A third project is directed at the development of fundamentally new classes of DNA-cleaving agents and potential cancer chemotherapeutics that are designed to function by the transition metal, photochemical, and torsional induction of diradical formation. A fourth major effort is focussed on taxol, a compound whose recent, impressive clinical performance is likely to result in its imminent approval for use in cancer chemotherapy. This study is directed at the development of practical approaches to taxol analogues and at the elucidation of the structural requirements for taxol's activity. A final project entails completion of studies on the synthesis of aplysiatoxin. Overall, this research program is expected to be of significant value in chemistry, biology, and medicine.
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