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 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.

Chemical generation and modification of peptides containing multiple dehydroalanines.

Chemical formation of dehydroalanine has been widely used for the post-translational modification of proteins and peptides, however methods to incorporate multiple dehydroalanine residues into a single peptide have not been defined. We report the use of methyl 2,5-dibromovalerate which can be used to cleanly carry out this transformation.