Congeners of the Enediyne Neocarzinostatin Chromophore: Designed Agents for bulged Nucleic Acid Targets

Author(s): Graham B. Jones, Yiqing Lin, Dong Ma, Ziwei Xiao, Geum-Sook Hwang, Lizzy Kappen, Irving H. Goldberg.

Journal Name: Current Topics in Medicinal Chemistry

Volume 8 , Issue 6 , 2008

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Abstract:

Of the commonly recognized structural elements within nucleic acids, bulges are among the least developed as targets for small molecules. Bulges in DNA and RNA have been linked to biomolecular processes involved in numerous diseases, thus probes with affinity for these targets would be of considerable utility to chemical biologists and medicinal chemists. Despite such opportunity, there is a dearth of small molecules available with affinity for bulges, which has hampered exploitation of these key targets. We have used guided chemical synthesis to prepare small molecules capable of binding to DNA and RNA bulges. Our design is based on a template which mimics a metabolite of the enediyne neocarzinostatin. The key spirocylic building block was formed through an intramolecular aldol process and the parent template shows pronounced affinity for 2 base bulges. Functionalization with specific aminosugar moieties confers nanomolar binding affinity for selected bulged DNA targets, and installation of reactive functional groups allows covalent modification of bulges. These rationally designed agents can now be used to study the stereochemistry and architecture of bulge-drug complexes and investigate the molecular biology of bulge induced processes. Members of this class have been shown to induce slipped synthesis of DNA, suggesting the agents, in addition to recognizing and binding to pre-formed bulges, can also induce bulge formation on demand.

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Article Details

VOLUME: 8
ISSUE: 6
Year: 2008
Page: [436 - 447]
Pages: 12
DOI: 10.2174/156802608783955692
Price: $58

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