This research program (CA-19033), now in the thirty-sixth year, embodies our long-term commitment to complete structural characterization and efficient enantiomeric synthesis of architecturally challenging agents, possessing bio-regulatory properties related to cancer chemotherapy. Specifically, we will demonstrate that Anion Relay Chemistry (ARC), a tactic introduced by our laboratory, holds great promise for the rapid, efficient construction of multi-gram quantities of stereo-defined, structurally complex synthetic intermediates and natural products having cancer cell growth inhibitory activities. Anion Relay Chemistry (ARC), the principal chemical innovation of this program, originated from a three-component union protocol, that comprises a [1,4]-Brook rearrangement to assemble complex arrays, employed initially for the total synthesis of the spongistatins 1 and 2. Subsequently, we generalized this concept to what we now term Anion Relay Chemistry (ARC). The proposed four-year application will significantly augment, demonstrate and showcase the utility of the ARC tactics for the rapid access to complex molecular architecture. With this introduction, the Specific Aims of years 37-40 will be: (A) to apply multiple iterations of the ARC three-component fragment union to achieve the rapid syntheses of polyol-containing anticancer natural products, including cryptocaryols A and B and the bastimolides A-C; (B) to develop a new ARC tactic to introduce branching points diastereoselectively on otherwise linear multi-component adducts. This tactic will be applied first to the total synthesis of anticancer natural product pterocidin. Given the unusual mechanism of action of pterocidin, the availability of the latter in significant quantity holds promise to open new doors in cancer biology. We will also: (C) showcase the utility of the ARC tactic for the total synthesis of the natural products nahuoic acid A and mandelalide A, both exhibiting nanomolar cytotoxicity against human cancer cell lines. In addition, we will: (D) develop a solid-supported variant of the ARC protocols to permit the rapid assembly of complex polyketide precursors with increased efficiency and virtually no purification. Finally, we will: (E) evaluate the cytotoxic/cancer biology of the natural products ad analogs thereof, through collaboration with world-class molecular pharmacologists. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of molecular architectures responsible for inhibition of tumor cell growth.
The overarching goal of this research program has been, and will continue to be, the full characterization, structural assignment, and efficient enantioselectie total syntheses of architecturally novel, naturally occurring compounds that hold significant potential as new chemotherapeutic agents to be evaluated for clinical intervention in the treatment of cancer. To this end, new synthetic chemistry involving Anion Relay 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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