We have been involved in the study of the biosynthesis of the potent anticancer antibiotic streptonigrin, and our work has revealed three new metabolic processes intend to initially confirm that the quinoline portion of the antibiotic is general by a new variation of the shikimate pathway. We will then identify the intermediates in the biosynthetic pathway through synthesis of putative aromatic intermediates, testing each through isotope trapping experiments, and following up positive leads by feeding labeled apparent intermediates. This will add significantly to our understanding of the organic chemistry of biological systems. We will also study the parameters necessary for, and the mechanism of, a laboratory analogy to the Beta-carboline ring cleavage reaction we have discovered. In order to extend our understanding of the biochemical variations of the shikimate pathway and of aromatic and heterocyclic chemestry, we are extending our work to include the novel antibiotic U-58,431 and the kinamycin antibiotics. The use of state-of-the-art NMR spectroscopic techniques will continue to be central to our work, as we will use 13C-13C spin couplings and homonuclear decoupling, 180-induced 13C chemical shifts, and 1H(2H) difference decoupling to reveal precursor relationships and define biochemical mechanisms.
