Molecular Recognition of DNA by Rigid [n]-Polynorbornane-Derived Bifunctional Intercalators: Synthesis and Evaluation of Their Binding Properties
We have exploited the concept of multivalency in the context of DNA recognition, using novel chemistry to synthesize a new type of bis-intercalator with unusual sequence-selectivity. Bis-intercalation has been observed previously, but design principles for de novo construction of such molecules are...
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Published in | Journal of medicinal chemistry Vol. 50; no. 10; pp. 2326 - 2340 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
17.05.2007
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
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Summary: | We have exploited the concept of multivalency in the context of DNA recognition, using novel chemistry to synthesize a new type of bis-intercalator with unusual sequence-selectivity. Bis-intercalation has been observed previously, but design principles for de novo construction of such molecules are not known. Our compounds feature two aromatic moieties projecting from a rigid, polynorbornane-based scaffold. The length and character of the backbone as well as the identity of the intercalators were varied, resulting in mono- or divalent recognition of the double helix with varying affinity. Our lead compound proved to be a moderately sequence-selective bis-intercalator with an unwinding angle of 27° and a binding constant of about 8 μM. 9-Aminoacridine rings were preferred over acridine carboxamides or naphthalimides, and a rigid [3]-polynorbornane scaffold was superior to a [5]-polynorbornane. The flexibility of the linker connecting the rings to the scaffold, although less influential, could affect the strength and character of the DNA binding. |
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Bibliography: | istex:56D4DB6682CE1019C3FEBD39A1E5B5D1A0B43EB4 ark:/67375/TPS-LR7FXFZN-7 Medline ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm0613020 |