This research program (CA-19033), now in the thirty-second year, embodies our long-term commitment to the complete structural characterization and efficient enantioselective synthesis of architecturally challenging anticancer agents. The principal goals for years 33-36 will comprise the following: In the phorboxazole area, we will: (A) scale up the synthesis of either (+)-phorboxazole A, (+)-chlorophorboxazole A, or a closely related analogue, based on the results of ongoing biological studies to define and optimal lead agents, and (B) prepare a series of probe molecules based on the selected phorboxazole lead to increase our understanding of the molecular mechanism(s) of action. In the lituarrine arena, we will: (C) complete the total syntheses of the revised structures of lituarines A-C, the latter based on detailed NMR and modeling studies carried out upon completion of the syntheses of the original """"""""assigned"""""""" structures. In the area of new targets, we will demonstrate the utility of the Petasis-Ferrier union/rearrangement with: (D) the total syntheses of enigmazoles A and B, members of an exciting new family of extremely rare marine agents that possess activities similar to Gleevec, and (E) with a total synthesis of tumor cell growth inhibitors (+)-neopeltolide, exploiting the Petasis-Ferrier tactic not only to construct the requisite tetrahydropyran ring, but also to achieve macrocyclization. In addition, we will: (F) develop and showcase the power of multicomponent Anion Relay Chemistry (ARC) with a viable synthesis of (+)-iriomoteolide 1a, a novel cytotoxic marine macrolide. Finally we will: (G) extend the non-aldol/polyene protocol for construction of stereochemically diverse polyketides. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of molecular architectures responsible for biological activity. Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships.
The overarching goal of this research program has been, and will continue to be, the full characterization, structural assignment, and efficient enantioselective total syntheses of architecturally novel, naturally occurring compounds that hold significant potential as new chemotherapeutic agents for clinical intervention in the treatment of cancer. To this end, new synthetic chemistry will be developed that will have utility not only for this program, but also be of general value to the academic and pharmaceutical communities engaged in Cancer Biology.
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