Abstract

The anti-tumor agent bleomycin is used clinically, both as a single agent and in combination chemotherapy for the treatment of several types of cancer. For example, bleomycin is efficacious against squamous cell carcinomas and malignant lymphomas. In spite of the obvious utility and importance of the bleomycins as antitumor agents, there are clear opportunities to alter the molecular behavior of bleomycin, and thereby potentially improve its antitumor efficacy. The long-term objectives of this research are the development of bleomycin analogues having improved antitumor efficacy, and an altered spectrum of anti-tumor activity. To achieve these goals, we will prepare libraries of BLM analogues by mix and split synthesis. These libraries will be used to select BLMs having specific desirable properties and the identified analogues will be characterized thoroughly as potential anti-tumor agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA077284-05A2
Application #
6685801
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Lees, Robert G
Project Start
1998-04-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$262,880
Indirect Cost

  Institution

Name
University of Virginia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
065391526
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
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
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
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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