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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA019033-36
Application #
8212072
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Misra, Raj N
Project Start
1976-06-30
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
36
Fiscal Year
2012
Total Cost
$245,060
Indirect Cost
$84,040
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chen, Ming Z; Gutierrez, Osvaldo; Smith 3rd, Amos B (2014) Through-bond/through-space anion relay chemistry exploiting vinylepoxides as bifunctional linchpins. Angew Chem Int Ed Engl 53:1279-82
Williams, Brett D; Smith 3rd, Amos B (2014) Total synthesis of (+)-18-epi-latrunculol A: development of a synthetic route. J Org Chem 79:9284-96
Shvartsbart, Artem; Smith 3rd, Amos B (2014) Total synthesis of (-)-calyciphylline N. J Am Chem Soc 136:870-3
An, Chihui; Jurica, Jon A; Walsh, Shawn P et al. (2013) Total synthesis of (+)-irciniastatin A (a.k.a. psymberin) and (-)-irciniastatin B. J Org Chem 78:4278-96
Nguyen, Minh H; Smith 3rd, Amos B (2013) Polymer-supported siloxane transfer agents for Pd-catalyzed cross-coupling reactions. Org Lett 15:4258-61
Williams, Brett D; Smith 3rd, Amos B (2013) Total synthesis of (+)-18-epi-latrunculol A. Org Lett 15:4584-7
Adams, Gregory L; Carroll, Patrick J; Smith 3rd, Amos B (2013) Access to the akuammiline family of alkaloids: total synthesis of (+)-scholarisine A. J Am Chem Soc 135:519-28
Melillo, Bruno; Smith 3rd, Amos B (2013) A unified synthetic strategy to the Cryptocarya family of natural products exploiting Anion Relay Chemistry (ARC). Org Lett 15:2282-5
Nguyen, Minh H; Smith 3rd, Amos B (2013) Copper-catalyzed electrophilic amination of organolithiums mediated by recoverable siloxane transfer agents. Org Lett 15:4872-5
Adams, Gregory L; Carroll, Patrick J; Smith 3rd, Amos B (2012) Total synthesis of (+)-scholarisine A. J Am Chem Soc 134:4037-40

Showing the most recent 10 out of 43 publications