Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers
Authors: Chen Haimei , Parkinson John A. , Nováková Olga , Bella Juraj , Wang Fuyi , Dawson Alice , Gould Robert , Parsons Simon , Brabec Viktor , Sadler Peter J. 
Published: December 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 η
6
-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((η
6
-biphenyl)RuCl(en))
2
-(CH
2
)
6
]
2
+
(3, en = ethylenediamine) was elucidated by studies of the half unit [(η
6
-biphenyl)RuCl(Et-en)]
+
(2, where Et-en is Et(H)NCH
2
CH
2
NH
2
). The structures of the separated

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and

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diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (
t
½
≈ 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the

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configurations are more stable than

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(73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to

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diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31°) of plasmid DNA, twice that of mononuclear 2 (14°), 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.