Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers.
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.
Chen
Haimei
H
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
Parkinson
John A
JA
Nováková
Olga
O
Bella
Juraj
J
Wang
Fuyi
F
Dawson
Alice
A
Gould
Robert
R
Parsons
Simon
S
Brabec
Viktor
V
Sadler
Peter J
PJ
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
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