Linked Life Data

18397167

Source:http://linkedlifedata.com/resource/pubmed/id/18397167

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2008-4-9
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1873-4294
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
8
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
436-47
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Congeners of the enediyne neocarzinostatin chromophore: designed agents for bulged nucleic acid targets.
pubmed:affiliation
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. Gr.jones@neu.edu
pubmed:publicationType
Journal Article