Abstract

(Principal Investigator's) The long term objectives of this program include the laboratory synthesis of complex natural products possessin desirable biological activity as well as the development of new synthetic methodology which will simplify this task. Specific natural products to be studied include the promising antitumor agent rhizoxin, structurally simplifie analogues of rhizoxin, and the highly cytotoxic marine natural product swinholide as well as misakinolide and scytophycin C, both of which are structurally very similar to swinholide. In addition, studies directed at tota syntheses of epothilone A & B and bryostatin 1 will be initiated. The epothilones are exciting new agents with biological activity very similar to taxol, and are thus important new structures of relevance to cancer chemotherapy. The potent new immunosuppressive agent pironetin will also be synthesized. The main thrust of the program, from a chemical point of view, is to develop new strategies and reactions which simplify the synthesis of these materials. An important focus of this research is the development of catalytic asymmetric reactions which allow for the formation of new stereogenic centers via union of two sp2 centers in a manner controlled by the catalyst.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028961-19
Application #
6179453
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1981-06-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
19
Fiscal Year
2000
Total Cost
$319,891
Indirect Cost

  Institution

Name
University of Utah
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Petersen, Mark E; Kedei, Noemi; Lewin, Nancy E et al. (2016) Replacement of the Bryostatin A- and B-Pyran Rings With Phenyl Rings Leads to Loss of High Affinity Binding With PKC. Tetrahedron Lett 57:4749-4753
Kelsey, Jessica S; Cataisson, Christophe; Chen, Jinqiu et al. (2016) Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin. Mol Carcinog 55:2183-2195
Kedei, Noemi; Kraft, Matthew B; Keck, Gary E et al. (2015) Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships. J Nat Prod 78:896-900
Kraft, Matthew B; Poudel, Yam B; Kedei, Noemi et al. (2014) Synthesis of a des-B-ring bryostatin analogue leads to an unexpected ring expansion of the bryolactone core. J Am Chem Soc 136:13202-8
Kedei, Noemi; Chen, Jin-Qiu; Herrmann, Michelle A et al. (2014) Molecular systems pharmacology: isoelectric focusing signature of protein kinase C? provides an integrated measure of its modulation in response to ligands. J Med Chem 57:5356-69
Kedei, N; Telek, A; Michalowski, A M et al. (2013) Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action. Biochem Pharmacol 85:313-24
Keck, Gary E; Poudel, Yam B; Rudra, Arnab et al. (2012) Role of the C8 gem-dimethyl group of bryostatin 1 on its unique pattern of biological activity. Bioorg Med Chem Lett 22:4084-8
Keck, Gary E; Poudel, Yam B; Cummins, Thomas J et al. (2011) Total synthesis of bryostatin 1. J Am Chem Soc 133:744-7
Kedei, Noemi; Telek, Andrea; Czap, Alexandra et al. (2011) The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line. Biochem Pharmacol 81:1296-308
Keck, Gary E; Poudel, Yam B; Rudra, Arnab et al. (2010) Molecular modeling, total synthesis, and biological evaluations of C9-deoxy bryostatin 1. Angew Chem Int Ed Engl 49:4580-4

Showing the most recent 10 out of 32 publications