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.

SUBMITTER: Chen H 

PROVIDER: S-EPMC299748 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature