This proposal is a request for funding to study the total synthesis of the recently discovered antitumor antibiotic quinocarcin (1,DC-52). Being the simplest member of the saframycin/naphthyridinomycin class of antibiotics, the synthetic protocol developed will focus on the asymmetric preparation of the isoquinoline nuclei and the bicyclic piperazines such that synthetic entries to naphthyridinomycin will be realized. It is the purpose of this proposal to establish the functional significance of the bicyclic piperazine moiety in imparting chemical stability manifested as biological reactivity in the DC-52 molecule. A mechanism of action is proposed and synthetic protocol will be established to probe both the covalent modification of DNA as well as the reported oxygen-dependent DNA strand scission by DC-52.
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 |