Abstract

(Principal Investigator's) The long term goals of this research are i) synthesis of bleomycin group antibiotics and the development of new methods that facilitate their elaboration, and ii) synthesis of bleomycin analogues that have superior properties as therapeutic agents or which can be used to help define the mechanism of action of bleomycin. For the period of requested support, the specific aims include completion of the total synthesis of phleomycin and a stereocontrolled, total synthesis of tallysomycin. Also planned are the syntheses of bleomycin analogues that can help to define the mode of DNA binding, which bind and cleave RNA with greater affinity, and which exhibit greater efficiency in double-strand cleavage of B-form DNA. While bleomycin is an established member of the armamentarium of clinically used antitumor agents, there are nonetheless a number of deficiencies in the understanding of the way in which BLM functions as an antitumor agent. The studies proposed here should facilitate an understanding of the mechanism of BLM action and make it possible to identify BLM congeners exhibiting enhanced properties as antitumor agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077284-04
Application #
6350272
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1998-04-01
Project End
2002-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
4
Fiscal Year
2001
Total Cost
$206,295
Indirect Cost

  Institution

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

  Publications

Ma, Qian; Xu, Zhidong; Schroeder, Benjamin R et al. (2007) Biochemical evaluation of a 108-member deglycobleomycin library: viability of a selection strategy for identifying bleomycin analogues with altered properties. J Am Chem Soc 129:12439-52
Leitheiser, Christopher J; Smith, Kenneth L; Rishel, Michael J et al. (2003) Solid-phase synthesis of bleomycin group antibiotics. Construction of a 108-member deglycobleomycin library. J Am Chem Soc 125:8218-27
Rishel, Michael J; Thomas, Craig J; Tao, Zhi-Fu et al. (2003) Conformationally constrained analogues of bleomycin A5. J Am Chem Soc 125:10194-205
Cagir, Ali; Tao, Zhi-Fu; Sucheck, Steven J et al. (2003) Solid-phase synthesis and biochemical evaluation of conformationally constrained analogues of deglycobleomycin A5. Bioorg Med Chem 11:5179-87
Thomas, Craig J; Chizhov, Alexander O; Leitheiser, Christopher J et al. (2002) Solid-phase synthesis of bleomycin A(5) and three monosaccharide analogues: exploring the role of the carbohydrate moiety in RNA cleavage. J Am Chem Soc 124:12926-7
Thomas, Craig J; McCormick, Michael M; Vialas, Corine et al. (2002) Alteration of the selectivity of DNA cleavage by a deglycobleomycin analogue containing a trithiazole moiety. J Am Chem Soc 124:3875-84
Smith, Kenneth L; Tao, Zhi-Fu; Hashimoto, Shigeki et al. (2002) Deglycobleomycin: solid-phase synthesis and DNA cleavage by the resin-bound ligand. Org Lett 4:1079-82
Zou, Ying; Fahmi, Nour Eddine; Vialas, Corine et al. (2002) Total synthesis of deamido bleomycin a(2), the major catabolite of the antitumor agent bleomycin. J Am Chem Soc 124:9476-88
Tao, Zhi-Fu; Leitheiser, Christopher J; Smith, Kenneth L et al. (2002) Solid-phase synthesis of deglycobleomycins: a C-terminal tetraamine linker that permits direct evaluation of resin-bound bleomycins. Bioconjug Chem 13:426-34
Rishel, M J; Hecht, S M (2001) Analogues of bleomycin: synthesis of conformationally rigid methylvalerates. Org Lett 3:2867-9

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