Van Vliet, L.Ellis, T.Foley, P.Liu, L.Pfeffer, F.Russell, R.Warrener, R.Hollfelder, F.Waring, M.2008-10-232008-10-232007Journal of Medicinal Chemistry, 2007; 50(10):2326-23400022-26231520-4804http://hdl.handle.net/2440/47991Copyright © 2007 American Chemical SocietyWe 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.enAmidesNorbornanesAcridinesAminoacridinesDeoxyribonucleasesDNAIntercalating AgentsDialysisElectrophoresis, Gel, Two-DimensionalStructure-Activity RelationshipNaphthalimidesJournal article002007075810.1021/jm06130200002463410000092-s2.0-3424908062348857