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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Misra, Raj N
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University of Pennsylvania
Schools of Arts and Sciences
United States
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Nguyen, Minh H; Imanishi, Masashi; Kurogi, Taichi et al. (2018) Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy. J Org Chem 83:4287-4306
Ai, Yanran; Kozytska, Mariya V; Zou, Yike et al. (2018) Total Synthesis of the Marine Phosphomacrolide, (-)-Enigmazole A, Exploiting Multicomponent Type I Anion Relay Chemistry (ARC) in Conjunction with a Late-Stage Petasis-Ferrier Union/Rearrangement. J Org Chem 83:6110-6126
Zou, Yike; Li, Xiangqin; Yang, Yun et al. (2018) Total Synthesis of (-)-Nodulisporic Acids D, C, and B: Evolution of a Unified Synthetic Strategy. J Am Chem Soc 140:9502-9511
Deng, Yifan; Liu, Qi; Smith 3rd, Amos B (2017) Oxidative [1,2]-Brook Rearrangements Exploiting Single-Electron Transfer: Photoredox-Catalyzed Alkylations and Arylations. J Am Chem Soc 139:9487-9490
Montgomery, Thomas D; Smith 3rd, Amos B (2017) ?-Silyl Amides: Effective Bifunctional Lynchpins for Type I Anion Relay Chemistry. Org Lett 19:6216-6219
Liu, Qi; Deng, Yifan; Smith 3rd, Amos B (2017) Total Synthesis of (-)-Nahuoic Acid Ci (Bii). J Am Chem Soc 139:13668-13671
Liu, Qi; Chen, Yu; Zhang, Xiao et al. (2017) Type II Anion Relay Chemistry: Conformational Constraints To Achieve Effective [1,5]-Vinyl Brook Rearrangements. J Am Chem Soc 139:8710-8717
Nazari, Mohamad; Serrill, Jeffrey D; Wan, Xuemei et al. (2017) New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors. J Med Chem 60:7850-7862
Nguyen, Minh H; Imanishi, Masashi; Kurogi, Taichi et al. (2016) Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol. J Am Chem Soc 138:3675-8
Adams, Gregory L; Smith 3rd, Amos B (2016) The Chemistry of the Akuammiline Alkaloids. Alkaloids Chem Biol 76:171-257

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