Investigating the chemical reactivity and biological activity of anti-tumor natural products is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of cancer. This research program aims to develop efficient synthesis of biologically active natural products possessing six-membered oxygen heterocycles through the development and subsequent application of new tactics and methodologies for organic synthesis. Strategies that generate the targeted natural products structures while providing broad solutions to synthesizing related families of compounds will be pursued. The targets selected for these investigations possess interesting and novel molecular architecture, lack significant prior synthetic studies, and have promising biological activity in the context of cancer. The planned synthetic approaches are designed to feature catalytic stereoselective pyran-forming reactions, the enantioselective synthesis of flavanones, and incorporate multiple bond forming sequences. The specific goals of this research are: (1) Synthesis of the natural products chrolactomycin and okilactomycin. These antitumor antibiotics possess a unique and highly oxygenated tricyclic core. We will use a new butenolide macrocyclization/conjugate addition approach as the key strategic sequence. (2) Total synthesis of exiguolide (3) Syntheses of flavanone natural products abyssinone II and kurarinone. We will employ a new enantioselective flavanone synthesis catalyzed by chiral thioureas for the syntheses of these compounds. (4) Evaluate all compounds in these studies for their activity against various human tumor cell lines including breast, prostate, colon, and pancreatic cancer. This last aim will be accomplished in a collaboration combining our synthetic knowledge and capabilities acquired in Aims 1-3 with two expert cancer researchers at Northwestern's Robert H. Lurie Comprehensive Cancer Center and one expert bioorganic chemist at Yale University

Public Health Relevance

This research program aims to develop efficient synthesis of biologically active natural products possessing oxygenate heterocycles through the development and subsequent application of new tactics and methodologies for organic synthesis. Investigating the chemical reactivity and biological activity of anti-tumor natural products is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA126827-02
Application #
7894732
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2009-07-16
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$275,174
Indirect Cost
Name
Northwestern University at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Lee, Ansoo; Betori, Rick C; Crane, Erika A et al. (2018) An Enantioselective Cross-Dehydrogenative Coupling Catalysis Approach to Substituted Tetrahydropyrans. J Am Chem Soc 140:6212-6216
McDonald, Benjamin R; Scheidt, Karl A (2015) Pyranone natural products as inspirations for catalytic reaction discovery and development. Acc Chem Res 48:1172-83
Nibbs, Antoinette E; Scheidt, Karl A (2012) Asymmetric Methods for the Synthesis of Flavanones, Chromanones, and Azaflavanones. European J Org Chem 2012:449-462
Crane, Erika A; Zabawa, Thomas P; Farmer, Rebecca L et al. (2011) Enantioselective synthesis of (-)-exiguolide by iterative stereoselective dioxinone-directed Prins cyclizations. Angew Chem Int Ed Engl 50:9112-5
Tenenbaum, Jason M; Morris, William J; Custar, Daniel W et al. (2011) Synthesis of (-)-okilactomycin by a Prins-type fragment-assembly strategy. Angew Chem Int Ed Engl 50:5892-5
Wang, Jingqi; Crane, Erika A; Scheidt, Karl A (2011) Highly stereoselective Bronsted acid catalyzed synthesis of spirooxindole pyrans. Org Lett 13:3086-9
Crane, Erika A; Scheidt, Karl A (2010) Prins-type macrocyclizations as an efficient ring-closing strategy in natural product synthesis. Angew Chem Int Ed Engl 49:8316-26
Farmer, Rebecca L; Biddle, Margaret M; Nibbs, Antoinette E et al. (2010) Concise syntheses of the abyssinones and discovery of new inhibitors of prostate cancer and MMP-2 expression. ACS Med Chem Lett 1:400-405
Nibbs, Antoinette E; Baize, Amanda-Lauren; Herter, Rachel M et al. (2009) Catalytic asymmetric alkylation of substituted isoflavanones. Org Lett 11:4010-3