Molekulární biofyzika a farmakologie
Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers
Publikace: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 100, 14623-14628 Autoři: Chen, HM., Parkinson, JA., Novakova, O., Bella, J., Wang, FY., Dawson, A., Gould, R., Parsons, S., Brabec, V., Sadler, PJ. Rok: 2003
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 R*R-Ru*(N) and S*R-Ru*(N) diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water t(1/2) approximate to 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the R*RuR*N configurations are more stable than S*RuR*N (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to S*RuR*N diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (310) of plasmid DNA, twice that of mononuclear 2 (14degrees), 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.