An Organometallic Compound which Exhibits a DNA Topology‐Dependent One‐Stranded Intercalation Mode. Issue 26 (17th May 2016)

• Record Type: Journal Article
• Authors: Ma, Zhujun; Palermo, Giulia; Adhireksan, Zenita; Murray, Benjamin S.; von Erlach, Thibaud; Dyson, Paul J.; Rothlisberger, Ursula; Davey, Curt A.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 26(2016)
• Page Start: 7441
• Page End: 7444
• Publication Date: 2016-05-17
• Subjects: anticancer agent -- DNA adducts -- intercalators -- molecular dynamics -- organometallics; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201602145
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Understanding how small molecules interact with DNA is essential since it underlies a multitude of pathological conditions and therapeutic interventions. Many different intercalator compounds have been studied because of their activity as mutagens or drugs, but little is known regarding their interaction with nucleosomes, the protein‐packaged form of DNA in cells. Here, using crystallographic methods and molecular dynamics simulations, we discovered that adducts formed by [(η 6 ‐THA)Ru(ethylenediamine)Cl][PF6 ] (THA=5, 8, 9, 10‐tetrahydroanthracene; RAED‐THA‐Cl[PF6 ]) in the nucleosome comprise a novel one‐stranded intercalation and DNA distortion mode. Conversely, the THA group in fact remains solvent exposed and does not disrupt base stacking in RAED‐THA adducts on B‐form DNA. This newly observed DNA binding mode and topology dependence may actually be prevalent and should be considered when studying covalently binding intercalating compounds. Abstract : Binding preferences : Using crystallographic methods and molecular dynamics simulations it was shown that adducts formed by the anticancer agent [(η 6 ‐5, 8, 9, 10‐tetrahydroanthracene)Ru(ethylenediamine)Cl][PF6 ] on a nucleosome comprise a novel one‐stranded intercalation and DNA distortion mode. The adduct dimorphism and DNA topology dependence might contribute to the unusually high cytotoxicity of this anticancer agent.