Abstract

The cellular targets of novel enediynes based on antitumor agents will be identified. To achieve this goal a small library of bifunctional enediynes will be chemically synthesized. These agents are designed to immobilize specific cellular targets, including DNA and proteins. Customized bioassay methods will be employed to delineate the required functionality to achieve in vitro biological activity against various tumor types. In tandem with this study, chemical interception of the diyl radicals derived from Bergman cycloaromatization will be investigated using a variety of atom transfer agents. It is expected that this will result in the chemical synthesis of numerous analogs of the cycloaromatized product which may have medicinal value in their own right. The study will throw new light on the mode of action of the enediynes and is expected to lead to the development of new antitumor agents and affinity cleavage systems.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM057123-01
Application #
2539060
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1997-09-30
Project End
1998-09-29
Budget Start
1997-09-30
Budget End
1998-09-29
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Clemson University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042629816
City
Clemson
State
SC
Country
United States
Zip Code
29634

  Publications

LaBeaume, Paul; Wager, Krista; Falcone, Danielle et al. (2009) Synthesis, functionalization and photo-Bergman chemistry of enediyne bioconjugates. Bioorg Med Chem 17:6292-300
Ma, Dong; Lin, Yiqing; Xiao, Ziwei et al. (2009) Designed DNA probes from the neocarzinostatin family: impact of glycosyl linkage stereochemistry on bulge base binding. Bioorg Med Chem 17:2428-32
Falcone, Danielle; Li, Jane; Kale, Amit et al. (2008) Photoactivated enediynes as targeted antitumoral agents: efficient routes to antibody and gold nanoparticle conjugates. Bioorg Med Chem Lett 18:934-7
Jones, Graham B; Lin, Yiqing; Xiao, Ziwei et al. (2007) Molecular probes of DNA bulges: functional assay and spectroscopic analysis. Bioorg Med Chem 15:784-90
Fouad, Farid S; Wright, Justin M; Plourde 2nd, Gary et al. (2005) Synthesis and protein degradation capacity of photoactivated enediynes. J Org Chem 70:9789-97
Lin, Yiqing; Jones, Graham B; Hwang, Geum-Sook et al. (2005) Convenient synthesis of NCS-chromophore metabolite isosteres: binding agents for bulged DNA microenvironments. Org Lett 7:71-4
Hwang, Geum-Sook; Jones, Graham B; Goldberg, Irving H (2004) Stereochemical control of small molecule binding to bulged DNA: comparison of structures of spirocyclic enantiomer-bulged DNA complexes. Biochemistry 43:641-50
Fouad, Farid S; Xi, Zhen; Goldberg, Irving H et al. (2004) Preparation of alkylation agents for bulged DNA microenvironments. Bioorg Med Chem Lett 14:3337-9
Hwang, Geum-Sook; Jones, Graham B; Goldberg, Irving H (2003) Solution structure of a wedge-shaped synthetic molecule at a two-base bulge site in DNA. Biochemistry 42:8472-83
Kappen, Lizzy S; Xi, Zhen; Jones, Graham B et al. (2003) Stimulation of DNA strand slippage synthesis by a bulge binding synthetic agent. Biochemistry 42:2166-73

Showing the most recent 10 out of 21 publications