The overall goal of this research program is to develop new and broadly useful methods and strategies and to apply these to the concise and efficient syntheses of biologically-active, heterocyclic natural products and analogs thereof that will serve as potential leads for developing novel therapeutic agents. This goal will be achieved by meeting specific objectives that fall into the two main categories of methodological studies and total synthesis. In the arena of synthetic methodology, we will: (1) Establish the versatility and practicality of our unified strategy for C-aryl glycoside synthesis;(2) Develop new methods for the facile synthesis of angular xanthone and anthracene derivatives;(3) Expand the scope of enantioselective and tandem ring closing metathesis reactions;(4) Develop tandem Staudinger/aza-Wittig/Ugi multicomponent reactions for the rapid synthesis of highly substituted glycine derivatives;(5) Discover tactics to effect enantioselective 1,4-additions of aryl reagents to 2-alkyl cycloalkenones;and (6) Develop new methods for the enantioselective synthesis of 2,2,5,5-tetrasubstituted tetrahydrofurans. In the arena of target directed synthesis, we will: (1) Complete the first synthesis of 5-hydroxyaloin A, a biologically active C-aryl glycoside;(2) Complete the first synthesis of the anticancer antibiotic kidamycin;(3) Complete the first synthesis of the anticancer agent pluramycin A and selected derivatives thereof containing replacements of the epoxide side chain and the sugar residues;(4) Complete the first synthesis of the anticancer agent IB-00208 and selected derivatives thereof containing a lactam ring in place of the lactone ring and replacements of the sugar residue;(5) Complete the first synthesis of the anticancer agent lundurine B;(6) Complete the first synthesis of the anticancer agent cortistatin A and selected derivatives thereof that contain different aryl substituents and variations of the amino diol array;(7) Determine the DNA alkylating specificities and activities of pluramycin A analogs and the stability of complexes of pluramycin-modified DNA with TATA binding proteins;and (8) Submit selected compounds to Merck Research Laboratories for biological evaluation, especially for anticancer activity, and to develop SARs for pluramycin A, IB-00208, and cortistatin A analogs in cellular assays to identify new cancer and other potential drug leads.. Two aspects of the proposed research are critical to public health. Firstly, the new methods that enable the synthesis of diverse structures incorporating heterocyclic rings will be of immeasurable use to chemists in the pharmaceutical industry and will facilitate their efforts to identify and develop new drug candidates. Secondly, the targets we have identified have significant potential as leads for the development of novel anticancer agents having improved biological profiles.
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