Abstract

The long-term objectives of this program include the laboratory synthesis of complex natural products possessing 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 simplified analogues of rhizoxin, and the highly cytotoxic marine natural product swinholide, as well as nisakinolide, and scytophycin C, both of which are structurally very similar to swinholide. The main thrust of the program is to develop new catalytic procedures for carbon-carbon bond formation using chiral Lewis acids to promote the union of two pi systems. Two new vicinal sp3 carbon centers can be generated in such reactions, and the aim is to control stereochemistry at these sites in both a relative and absolute sense. Specific examples which will be studied represent reactions between aldehydes and allylstannanes or allylsilanes spanning a wide range of structural types; these reactions represent catalytic alternatives to the most powerful enantioselective synthetic reactions presently available.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028961-16
Application #
2391891
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1981-06-01
Project End
1998-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
16
Fiscal Year
1997
Total Cost
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

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