Abstract

It is proposed to synthesize and study natural and nonnatural members of a class of compounds capable of forming biradicals under physiological conditions with the tandem goals (1) to increase our understanding of the detailed mechanisms by which these substances cleave DNA and function as antitumor agents; and (2) to provide by chemical synthesis new structures for study as potential DNA cleaving agents and as leads for the design of new antitumor agents. This is a multifaceted program which is composed of the following subdivisions: (a) Synthesis of Neocarzinostatin Chromophore, its Aglycone, and Nonnatural Derivatives of the Chromophore Core; (b) Synthesis and Study of Dynemicin and Related Structures; (c) Design and Synthesis of Nonnatural DNA Cleaving Agents; (d) Mechanistic Studies of Natural and Nonnatural DNA Cleaving Agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047148-08
Application #
2092448
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1988-04-01
Project End
1998-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
8
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125

  Publications

Mortison, Jonathan D; Schenone, Monica; Myers, Jacob A et al. (2018) Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures. Cell Chem Biol 25:1506-1518.e13
Andresen, Vibeke; Erikstein, Bjarte S; Mukherjee, Herschel et al. (2016) Anti-proliferative activity of the NPM1 interacting natural product avrainvillamide in acute myeloid leukemia. Cell Death Dis 7:e2497
Mukherjee, Herschel; Chan, Kok-Ping; Andresen, Vibeke et al. (2015) Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML-associated mutants. ACS Chem Biol 10:855-63
Blasdel, Landy K; Lee, DongEun; Sun, Binyuan et al. (2013) (S)-4-Trimethylsilyl-3-butyn-2-ol as an auxiliary for stereocontrolled synthesis of salinosporamide analogs with modifications at positions C2 and C5. Bioorg Med Chem Lett 23:6905-10
Magauer, Thomas; Smaltz, Daniel J; Myers, Andrew G (2013) Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues. Nat Chem 5:886-93
Hugelshofer, Cedric L; Mellem, Kevin T; Myers, Andrew G (2013) Synthesis of quaternary ?-methyl ?-amino acids by asymmetric alkylation of pseudoephenamine alaninamide pivaldimine. Org Lett 15:3134-7
Mellem, Kevin T; Myers, Andrew G (2013) A simple, scalable synthetic route to (+)- and (-)-pseudoephenamine. Org Lett 15:5594-7
Morales, Marvin R; Mellem, Kevin T; Myers, Andrew G (2012) Pseudoephenamine: a practical chiral auxiliary for asymmetric synthesis. Angew Chem Int Ed Engl 51:4568-71
Smaltz, Daniel J; Švenda, Jakub; Myers, Andrew G (2012) Diastereoselective additions of allylmetal reagents to free and protected syn-?,?-dihydroxyketones enable efficient synthetic routes to methyl trioxacarcinoside A. Org Lett 14:1812-5
Svenda, Jakub; Hill, Nicholas; Myers, Andrew G (2011) A multiply convergent platform for the synthesis of trioxacarcins. Proc Natl Acad Sci U S A 108:6709-14

Showing the most recent 10 out of 19 publications