Molecular Recognition of DNA by Rigid [n]-Polynorbornane-Derived Bifunctional Intercalators:  Synthesis and Evaluation of Their Binding Properties

• Published in: Journal of medicinal chemistry Vol. 50; no. 10; pp. 2326 - 2340
• Main Authors: Van Vliet, Liisa D, Ellis, Tom, Foley, Patrick J, Liu, Ligong, Pfeffer, Frederick M, Russell, Richard A, Warrener, Ronald N, Hollfelder, Florian, Waring, Michael J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.05.2007; Amer Chemical Soc
• Subjects: Acridines - chemical synthesis; Acridines - chemistry; Amides - chemical synthesis; Amides - chemistry; Aminoacridines - chemical synthesis; Aminoacridines - chemistry; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Chemistry, Medicinal; Deoxyribonucleases - chemistry; Dialysis; DNA - chemistry; Dna, deoxyribonucleoproteins; Electrophoresis, Gel, Two-Dimensional; Fundamental and applied biological sciences. Psychology; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Naphthalimides - chemical synthesis; Naphthalimides - chemistry; Norbornanes - chemical synthesis; Norbornanes - chemistry; Nucleic acids; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; ANTITUMOR AGENTS; CONSTANTS; TRIOSTIN-A; AMINO-ACIDS; SEQUENCE; EQUILIBRIUM; COMPLEXES; DIACRIDINES; UNWINDING ANGLES; DITERCALINIUM; Molecular rigidity; Imide; Intercalating agent; Acridine derivatives; DNA; Epoxide; Molecular recognition; Steric hindrance; Stability constant; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0613020

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.