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
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA047148-14
Application #
6350080
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1988-04-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
14
Fiscal Year
2001
Total Cost
$641,685
Indirect Cost

  Institution

Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

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
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
Si, Chong; Myers, Andrew G (2011) A versatile synthesis of substituted isoquinolines. Angew Chem Int Ed Engl 50:10409-13
Simmons, Rebecca L; Yu, Robert T; Myers, Andrew G (2011) Storable arylpalladium(II) reagents for alkene labeling in aqueous media. J Am Chem Soc 133:15870-3

Showing the most recent 10 out of 16 publications