The specific aims of the last proposal entitled """"""""Antitumor Agents: Bouvardin and Luzopeptins"""""""" have been completed or are the focus of current efforts. Following efforts that first led to the total synthesis of isodityrosine, the ACE I inhibitor K-13, the aminopeptidase B inhibitors OF4949-III and OF4949-IV, and the cytotoxic agent combretastatin D-2, the efforts in this grant period have been extended to define the scope of an intramolecular Ullmann biaryl ether coupling reaction for macrocyclization closure of refractory 14-membered biaryl ethers. Its use in the total synthesis of bouvardin and O-methyl bouvardin has been completed. This methodology provided the opportunity to prepare key partial structures and analogs of the natural products that led to the completion of studies that define the structural and conformational properties that contribute to their biological properties. Importantly, this was possible only through implementation of the developed biaryl ether macrocyclization reaction by which the refractory 14-membered cycloisodityrosine-derived biaryl ethers have become synthetically accessible (30-60 percent) for such studies. Preliminary studies on the natural extension of this methodology for the preparation of vancomycin and structurally related antibiotics have been completed including the development of a substantial improvement through use of an intramolecular SnAr macrocyclization reaction (70-80 percent). These studies insure a straightforward approach to the proposed efforts on vancomycin to be conducted in the next grant period. In addition, the total synthesis of (-)-sandramycin was completed in this last grant period which served to unambiguously establish its relative and nonobvious absolute stereochemistry. These studies have been extended to a definition of its DNA binding properties (binding affinity, bisintercalation, 5'-NATN bisintercalation sequence selectivity with a preference for 5'CATG). Important information on the structural origin of these properties (minor groove binding cyic decadepsipeptide with stabilizing intercalation) has been derived from the studies to date. Similarly, a systematic and complete study of the role of the intercalating chromophores are in the process of being defined. These studies will continue in the new grant period along with extensions to the total synthesis of the luzopeptins and the accompanying SAR studies. Exciting new studies on the design, synthesis, and evaluation of DNA alkylation, cross-linking and cleaving agents based on the sandramycin template structure are detailed.
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