The aim of the proposed research is to discover and develop unique, non-intercalative inhibitors of DNA topoisomerase II as potential antineoplastic agents. Prior studies on synthetic topoisomerase II agents led to a model pharmacophore that assimilated the structural elements of many intercalative and non-intercalative classes of agents. Based on these studies, the prototype agent azatoxin was designed. Azatoxin is a potent inducer of topoisomerase II -bound DNA strand breaks. Studies of structure-activity relationships of azatoxin and related compounds as well as consideration of work published by others has helped to refine the model.
The specific aims are to synthesize unique structural classes of topoisomerase II-directed agents that (1) incorporate the anthracycline-epipodophyllotoxin/azatoxin/qunotoxin nuclei (2) possess the DNA intercalation-minor groove binding motif proposed in their model and (3) that possess the potential to undergo significant structural alteration upon bioreduction or glutathione conjugation and/or by hypoxic conditions (4) that are non-intercalative and have the potential for photoactivated crosslinking to DNA while bound to the cleavable complex and (5) that possess defined conformational relationships between the minor groove binding and DNA intercalation domains in their model. Finally, in an attempt to provide new information on the mechanism of topoisomerase II poison cytotoxicity, they will compare the sensitivity of the alpha and beta isozymes of topoisomerase II to the different analogs, quantitate the levels of single and double strand DNA breaks and possibly through a collaboration, the intensity of drug-induced in vitro cleavage activity in the ras protooncogene.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054347-07
Application #
2733020
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Johnson, George S
Project Start
1991-03-01
Project End
1999-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Virginia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Madalengoitia, J S; Tepe, J J; Werbovetz, K A et al. (1997) Structure-activity relationship for DNA topoisomerase II-induced DNA cleavage by azatoxin analogues. Bioorg Med Chem 5:1807-15
Cline, S D; Macdonald, T L; Osheroff, N (1997) Azatoxin is a mechanistic hybrid of the topoisomerase II-targeted anticancer drugs etoposide and ellipticine. Biochemistry 36:13095-101
Tepe, J J; Madalengoitia, J S; Slunt, K M et al. (1996) Inhibition of DNA topoisomerase II by azaelliptitoxins functionalized in the variable substituent domain. J Med Chem 39:2188-96
Slunt, K M; Grace, J M; Macdonald, T L et al. (1996) Effect of mitonafide analogs on topoisomerase II of Leishmania chagasi. Antimicrob Agents Chemother 40:706-9
Werbovetz, K A; Spoors, P G; Pearson, R D et al. (1994) Cleavable complex formation in Leishmania chagasi treated with anilinoacridines. Mol Biochem Parasitol 65:1-10
Werbovetz, K A; Lehnert, E K; Macdonald, T L et al. (1992) Cytotoxicity of acridine compounds for Leishmania promastigotes in vitro. Antimicrob Agents Chemother 36:495-7
Leteurtre, F; Madalengoitia, J; Orr, A et al. (1992) Rational design and molecular effects of a new topoisomerase II inhibitor, azatoxin. Cancer Res 52:4478-83