Abstract

This proposal seeks to consolidate existing/pending grant support into a single grant, as defined by guidelines for the National Cancer Institute Outstanding Investigator Grant. Activities under the award would include continuing investigation of the bleomycin group antibiotics, development of novel strategies for the manipulation (principally strand scission) of nucleic acids under conditions that can obtain in intact cells, and the utilization of misacylated tRNA's to elaborate """"""""synthetic enzymes"""""""" for study. These enzymes will be key target enzymes for cancer chemotherapy (eg, dihydrofolate reductase) that contain synthetic amino acids at predetermined positions capable of facilitating precise analysis of the underlying chemistry of enzyme function, and hence can guide the synthesis of improved enzyme inhibitors that are of interest as antitumor agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA053913-03
Application #
3479819
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1991-05-15
Project End
1998-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of Virginia
Department
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Keck, M V; Manderville, R A; Hecht, S M (2001) Chemical and structural characterization of the interaction of bleomycin A2 with d(CGCGAATTCGCG)2. efficient, double-strand DNA cleavage accessible without structural reorganization. J Am Chem Soc 123:8690-700
Sznaidman, M L; Hecht, S M (2001) Studies on the total synthesis of tallysomycin. Synthesis of the threonylbithiazole moiety containing a structurally unique glycosylcarbinolamide. Org Lett 3:2811-4
Zhou, B N; Johnson, R K; Mattern, M R et al. (2000) Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon. J Nat Prod 63:217-21
Hecht, S M (2000) Bleomycin: new perspectives on the mechanism of action. J Nat Prod 63:158-68
Wang, X; Zhou, X; Hecht, S M (1999) Role of the 20-hydroxyl group in camptothecin binding by the topoisomerase I-DNA binary complex. Biochemistry 38:4374-81
Arslan, T; Abraham, A T; Hecht, S M (1998) DNA duplexes containing 3'-deoxynucleotides as substrates for DNA topoisomerase I cleavage and ligation. J Biol Chem 273:12383-90
Wang, X; Wang, L K; Kingsbury, W D et al. (1998) Differential effects of camptothecin derivatives on topoisomerase I-mediated DNA structure modification. Biochemistry 37:9399-408
Arslan, T; Abraham, A T; Hecht, S M (1998) Structurally altered substrates for DNA topoisomerase I. Effects of inclusion of a single 3'-deoxynucleotide within the scissile strand. Nucleosides Nucleotides 17:515-30
Wang, X; Henningfeld, K A; Hecht, S M (1998) DNA topoisomerase I-mediated formation of structurally modified DNA duplexes. Effects of metal ions and topoisomerase I inhibitors. Biochemistry 37:2691-700
Holmes, C E; Duff, R J; van der Marel, G A et al. (1997) On the chemistry of RNA degradation by Fe.bleomycin. Bioorg Med Chem 5:1235-48

Showing the most recent 10 out of 21 publications