Molecular recognition of DNA by rigid [N]-polynorbornane-derived bifunctional intercalators: synthesis and evaluation of their binding properties

J Med Chem. 2007 May 17;50(10):2326-40. doi: 10.1021/jm0613020. Epub 2007 Apr 13.


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 degrees and a binding constant of about 8 microM. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemical synthesis*
  • Acridines / chemistry
  • Amides / chemical synthesis
  • Amides / chemistry
  • Aminoacridines / chemical synthesis
  • Aminoacridines / chemistry
  • DNA / chemistry*
  • Deoxyribonucleases / chemistry
  • Dialysis
  • Electrophoresis, Gel, Two-Dimensional
  • Intercalating Agents / chemical synthesis*
  • Intercalating Agents / chemistry
  • Naphthalimides / chemical synthesis
  • Naphthalimides / chemistry
  • Norbornanes / chemical synthesis*
  • Norbornanes / chemistry
  • Structure-Activity Relationship


  • Acridines
  • Amides
  • Aminoacridines
  • Intercalating Agents
  • Naphthalimides
  • Norbornanes
  • dimethyl 6,,16-(2',2''-di-(9'''-acridinylamino)ethyl)-6,16-diaza-21-oxaoctacyclo(,9)1.(13,19)0.(2,10)0.(4,8)0.(12,20)0.(14,18))tricosane-5,7,15,17-tetraone-1,11-dicarboxylate
  • DNA
  • Deoxyribonucleases