The pyrrolidinyl-spiroxindole substructure is found in a variety of bioactive compounds, natural and unnatural in origin, that have received significant attention as potential anti-cancer agents. The Gardneria oxindole natural products, which include the monomers chitosenine and gardneramine and the heterodimer gardmultine, contain this heterocyclic motif and have been shown to possess a range of biological activities. Of particular interest is their cytotoxic activity against a p-glycoprotein overexpressing cell-line and potent in vitro reversal of multidrug resistance to the anti-cancer agents vincristine and doxorubicin. Additionally, in vivo inhibition of ganglionic transmission has been demonstrated resulting from proposed binding to the nicotinic receptor. Despite this remarkable bioactivity, there are no synthetic methods leading to these agents;a deficiency which inhibits further study of these biological properties. This proposal will develop enantioselective synthetic approaches to these natural products through the examination of two distinct methodologies to generate the ring systems attached to the oxindole nucleus. The first approach will incorporate a tandem Heck/p-allyl capture reaction to set the key adjacent stereocenters in a single step. A complementary approach, featuring a Heck cyclization followed by a highly novel intramolecular Petasis boronic Mannich ring synthesis, will also be explored. With access to the two monomeric natural products using these methods, the generation of the highly complex heterodimer gardmultine will then be examined. Biological evaluation of these natural products, as well as key derivatives, will be completed. This work is anticipated to directly lead to the generation of related analogs that may possess additional useful bioactivity. Furthermore, synthetic methodologies developed in the course of this work will find further use in synthesis, as motifs found in these compounds are present in a number of biologically relevant molecules.

Public Health Relevance

This proposal seeks to develop the methods needed to perform the chemical synthesis of a promising class of anti-cancer natural products. Synthetic approaches towards these compounds will enable further studies of their biological properties, as well as permitting the generation of analogs with structural modifications that should improve their usefulness. Studies of this type play a crucial role in the drug development process;as a source of clinical candidates, for the generation of chemical tools for the study of biological function, and for the development of chemical methods applicable to the synthesis of other novel agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA138084-02
Application #
7779940
Study Section
Special Emphasis Panel (ZRG1-F04A-T (20))
Program Officer
Myrick, Dorkina C
Project Start
2009-01-28
Project End
2012-01-27
Budget Start
2010-01-28
Budget End
2011-01-27
Support Year
2
Fiscal Year
2010
Total Cost
$47,606
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Schnermann, Martin J; Untiedt, Nicholas L; Jimenez-Oses, Gonzalo et al. (2012) Forming tertiary organolithiums and organocuprates from nitrile precursors and their bimolecular reactions with carbon electrophiles to form quaternary carbon stereocenters. Angew Chem Int Ed Engl 51:9581-6
Schnermann, Martin J; Overman, Larry E (2012) A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition. Angew Chem Int Ed Engl 51:9576-80
Schnermann, Martin J; Beaudry, Christopher M; Genung, Nathan E et al. (2011) Divergent synthesis and chemical reactivity of bicyclic lactone fragments of complex rearranged spongian diterpenes. J Am Chem Soc 133:17494-503
Schnermann, Martin J; Overman, Larry E (2011) Enantioselective total synthesis of aplyviolene. J Am Chem Soc 133:16425-7
Schnermann, Martin J; Beaudry, Christopher M; Egorova, Anastasia V et al. (2010) Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core. Proc Natl Acad Sci U S A 107:6158-63