The long-term objectives of this research are the development of bleomycin analogues having improved antitumor efficacy, and an altered spectrum of antitumor activity. For the period of requested support, the specific aims include the identification of BLM analogues with altered functional properties at a molecular level. Key parameters of function include mode and selectivity of DNA and RNA cleavage, targeting of specific RNAs and resistance to degradation. The antitumor 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076297-08
Application #
6909822
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Lees, Robert G
Project Start
1997-12-10
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
8
Fiscal Year
2005
Total Cost
$256,600
Indirect Cost
Name
University of Virginia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Akiyama, Yoshitsugu; Ma, Qian; Edgar, Erin et al. (2008) Identification of strong DNA binding motifs for bleomycin. J Am Chem Soc 130:9650-1
Akiyama, Yoshitsugu; Ma, Qian; Edgar, Erin et al. (2008) A novel DNA hairpin substrate for bleomycin. Org Lett 10:2127-30
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Tao, Zhi-Fu; Konishi, Kazuhide; Keith, Gerard et al. (2006) An efficient mammalian transfer RNA target for bleomycin. J Am Chem Soc 128:14806-7
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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

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