This research program (CA-19033), now in the fortieth 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, and now Radical Relay Chemistry (RRC), 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 early 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, and in turn the synthesis of the frog alkaloid 205B and indolizidine 223AB. Subsequently, we generalized this concept to what we now term Anion Relay Chemistry (ARC). More recently we added the tactic of Radical Relay Chemistry. This five-year renewal application will significantly augment, demonstrate and showcase the utility of both ARC and RRC tactics for the rapid, and now in a potentially multi-iteration format, access to complex molecular fragments (vide infra), readily available from enantiomerically pure starting materials. With this introduction, the Specific Aims for years 41-45 will be: (A) apply our highly flexible ARC multi-component fragment union protocols to achieve rapid access to polyol- containing anticancer products, including neaumycin B, bastimolide A, penniciketal A and (-)- pterocidin; (B) exploit our innovative ARC [3+2] annulation for the syntheses of euphornin L; (C) showcase our ?Through-Bond/Through-Space? ARC tactic for the construction the cytotoxic agents pyxipyrrolones A and B; (D) demonstrate the innovative use of Radical Relay Chemistry (RRC) to construct the complex spiroketallactone structures for the synthesis of the cytotoxic agents, the sequoiamonascins; (E) demonstrate diversity-oriented synthesis for the rare members of the nahuoic acid family of SETD8 inhibitors; and (F) continue our active collaborations to evaluate the cancer biology of these anticancer agents. Beyond these synthetic objectives, a general, long-range goal of this program is the identification of molecular receptors responsible for biological activity. Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit elucidation of structure-activity relationships to be defined by our biological collaborators.
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 to be evaluated for clinical intervention in the treatment of cancer. To this end, new synthetic chemistry involving Anion Relay Chemistry, now with Radical 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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