Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers

doi:10.1073/pnas.2434016100

Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers

^†School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom; ^‡Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XQ, United Kingdom; and ^§Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265, Brno, Czech Republic

Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved October 7, 2003 (received for review July 1, 2003)

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 η⁶-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((η⁶-biphenyl)RuCl(en))₂-(CH₂)₆]² ⁺ (3, en = ethylenediamine) was elucidated by studies of the half unit [(η⁶-biphenyl)RuCl(Et-en)]⁺ (2, where Et-en is Et(H)NCH₂CH₂NH₂). The structures of the separated $\text{[math]}$ and $\text{[math]}$ 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 $\text{[math]}$ configurations are more stable than $\text{[math]}$ (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to $\text{[math]}$ 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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: brabec{at}ibp.cz or p.j.sadler{at}ed.ac.uk.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Bip, biphenyl; dien, diethylenetriamine; CT, calf thymus; en, ethylenediamine; 9EtG, 9-ethylguanine.
Data deposition: The x-ray crystal structures of complexes 2A, 2B, and 4 have been deposited in the Cambridge Structural Database, Cambridge Crystallographic Data Centre, Cambridge CB2 1EZ, United Kingdom, (CSD reference nos. 223919, 223918, and 223917, respectively).
↵ ∥ The formal absolute configuration at Ru was determined by using the general priority order: Bip > Cl/O/N7 > N2 > N1 for diastereomers 2A(Cl, H₂O), 2B(Cl, H₂O), and 4(N7-9EtG) (28). No CD signals were detected for 2A, 2B, or 4 in DMSO or water, consistent with each diastereomer being present as an enantiomeric pair in a 1:1 ratio as in the crystals.
↵ †† NMR data for the 5′ GMP adducts [(η⁶-Bip)Ru(N7-5′GMP)(Et-en)]²⁺ (H8: 8.73 and 8.82 ppm) and [((η⁶-Bip)Ru(N7-5′GMP)(en))₂-(CH₂)₆]⁴⁺ (H8: 8.72 and 8.83 ppm) are consistent with this interpretation. ¹H NMR peaks for the S _Ru R _N-(β-D) and R _Ru S _N-(β-D) diastereomers were present in a 1:1 mol ratio (10% D₂O, pH 7.2), suggesting that there may be no enantioselectivity between S _Ru R _N and R _Ru S _N for DNA binding.