This proposal is a continuing request to study the biomechanism of the anti-tumor antibiotic Quinocarcin (DC-52). Quinocarcin has been shown to effect oxygen-dependent lesions in DNA by a novel, and as yet, unknown mechanism. The primary objective of this program is to elucidate the mechanism of this process, and develop a structural hypothesis embracing this reaction that could be extended to other systems. Related to this investigation is the objective of sorting out whether quinocarcin and related anti-tumor antibiotics have multiple modes of action such as sequence-specific binding and/or intercalation; alkylation of DNA; and oxidative scission of DNA. We propose to study and elucidate the sequence specificity (if any) of the interaction of quinocarcin with DNA and to further elucidate which type of interaction is responsible for cytotoxicity. We have rigorously established that pure quinocarcin plus oxygen alone can effect the scission of DNA that is independent of added metal ions or reducing agents; these results confirm earlier reports by Tomita, et. al. It is proposed that the labile and crucial oxazolidine moiety is the reductant capable of producing oxygen and/or hydroxyl free radicals and is also likely responsible for alkylation of DNA. Experiments will be aimed at elucidating the mechanistic details of this novel reaction and to determine the significance of this reaction to the anti-tumor properties of the drug. A second, and unrelated (to the above) portion of this proposal is a continuing request to study the total synthesis and biogenesis of the natural mycotoxins, paraherquamide and marcfortines A-C. It has recently been learned that paraherquamide displays potent anti-parasitic properties and has been the subject of intensive investigation at Merck. The purpose of this investigation is to prepare that natural products, establish their biogenetic pathways and synthesize both hypothetical shunt metabolites as well as analogs to develop a structure-activity profile of this complex class of alkaloids.
| Herberich, B; Scott, J D; Williams, R M (2000) Synthesis of a netropsin conjugate of a water-soluble epi-quinocarcin analogue: the importance of stereochemistry at nitrogen. Bioorg Med Chem 8:523-32 |
| Hefner, J; Rubenstein, S M; Ketchum, R E et al. (1996) Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5alpha-ol: the first oxygenation step in taxol biosynthesis. Chem Biol 3:479-89 |
| Flanagan, M E; Rollins, S B; Williams, R M (1995) Netropsin and spermine conjugates of a water-soluble quinocarcin analog: analysis of sequence-specific DNA interactions. Chem Biol 2:147-56 |
| Williams, R M; Flanagan, M E; Tippie, T N (1994) O2-dependent cleavage of DNA by tetrazomine. Biochemistry 33:4086-92 |
