title: Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers.
abstract: Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by eta 6-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((eta 6-biphenyl)RuCl(en))2-(CH2)6]2 + (3, en = ethylenediamine) was elucidated by studies of the half unit [(eta 6-biphenyl)RuCl(Et-en)]+ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated RRu*RN* and SRu*RN* diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t(1/2) approximately 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the RRu*RN* configurations are more stable than SRu*RN* (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to SRu*RN* diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31 degrees) of plasmid DNA, twice that of mononuclear 2 (14 degrees), and effectively inhibited DNA-directed RNA synthesis in vitro. This dinuclear complex gave rise to interstrand cross-links on a 213-bp plasmid fragment with efficiency similar to bifunctional cisplatin, and to 1,3-GG interstrand and 1,2-GG and 1,3-GTG intrastrand cross-links on site-specifically ruthenated 20-mers. Complex 3 blocked intercalation of ethidium considerably more than mononuclear 2. The concept of induced-fit recognition of DNA by organometallic complexes containing dynamic stereogenic centers via dynamic epimerization, intercalation, and cross-linking may be useful in the design of anticancer drugs.
authors.affiliation: School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
authors.forename: Haimei
authors.initials: H
authors.lastname: Chen
authors.forename: John A
authors.initials: JA
authors.lastname: Parkinson
authors.forename: Olga
authors.initials: O
authors.lastname: Nováková
authors.forename: Juraj
authors.initials: J
authors.lastname: Bella
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
authors.forename: Alice
authors.initials: A
authors.lastname: Dawson
authors.forename: Robert
authors.initials: R
authors.lastname: Gould
authors.forename: Simon
authors.initials: S
authors.lastname: Parsons
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002942:Circular Dichroism; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004278:DNA, Superhelical / Q000737:chemistry; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry; D004996:Ethidium / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000378:metabolism; D013237:Stereoisomerism; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004278:DNA, Superhelical; D006147:Guanine; C014542:9-ethylguanine; D004247:DNA; D012321:DNA-Directed RNA Polymerases; D004996:Ethidium; D002945:Cisplatin