Abstract

The proposed research involves the study and development of a variety of carbon-carbon bond forming reactions which are particularly well suited for use in the synthesis of natural products possessing desirable antibiotic or antitumor activity, and the application of these methods to total syntheses of such compounds. Specific examples include antibiotics such as colletodiol, calcimycin, carbomycin and tylosin, as well as the antitumor agent herbimycin. A synthetic investigation of the very promising rhizoxin family of antitumor agents, designed not only to culminate in a successful laboratory synthesis but also to reveal structural features required for activity and to provide simpler biologically active analogues, is also proposed as an example of how such methodology allows for particularly concise syntheses of biologically important compounds.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028961-12
Application #
3276358
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1981-06-01
Project End
1994-05-31
Budget Start
1992-06-01
Budget End
1994-05-31
Support Year
12
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Utah
Department
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
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; Cummins, Thomas J et al. (2011) Total synthesis of bryostatin 1. J Am Chem Soc 133:744-7
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