Liu, Hong-Ke, Parkinson, J. A. (John A.), Bella, Juraj, Wang, Fuyi and Sadler, P. J.. (2010) Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene Ru-II anticancer complex. Chemical Science, Vol.1 (No.2). pp. 258-270. ISSN 2041-6520

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Abstract

The organometallic Ru-II arene complex [(eta(6)-tha) Ru(en)Cl](+) (1), where tha tetrahydroanthracene and en = ethylenediamine, is potently cytotoxic towards cancer cells. We have used a combination of HPLC, ESI-MS, 1D- and 2D-NMR, including [H-1, H-1] ROESY, NOESY, [H-1, N-15] HSQC (using N-15-1), and [H-1, P-31] experiments to elucidate the role of the non-aromatic, bulky rings of tha in adducts with the DNA hexamer d(CGGCCG), since DNA is a potential target for this drug. Reactions of 1 with single-stranded d(CGGCCG) gave rise to ruthenation at each of the three G bases, whereas reactions of the duplex d(CGGCCG)(2) with 1 mol equiv. 1 led to exclusive ruthenation of G(3) and G(6) (and G(9), G(12)) and not G(2) (or G(8)). Addition of a second mol equiv. of 1 gave di-ruthenated adducts (major sites G(3)/G(6), G(6)/G(9), G(2)/G(6)), and on reaction with a third mol equiv. tri-ruthenation (G(2), G(3)/G(6)/G(12)). The NMR data are indicative of the coordinative binding of Ru-tha specifically to G(3) and G(6), together with penetrative intercalation of the bulky non-coordinated tha rings B and C of 1', selectively between two base pairs G(3)/C-10:C-4/G(9) and G(6)/C-7:C-5/G(8). Intercalation at GpC base steps by tha has a lower energy penalty compared to intercalation at GpG base steps, thereby allowing accommodation of tha. Mono-intercalation of tha reduced the strength of H-bonding between en-NH and GO6. These differences in structural distortions compared to cisplatin induced by the coordinative binding of Ru-tha to GN7 may contribute to the differences in mechanism of action, including protein recognition of the metallated lesions, and lack of cross resistance.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RS Pharmacy and materia medica
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Ruthemium compounds, Aromatic compounds, Antineoplastic agents, Organometallic compounds, DNA-drug interactions
Journal or Publication Title:	Chemical Science
Publisher:	Royal Society of Chemistry
ISSN:	2041-6520
Date:	August 2010
Volume:	Vol.1
Number:	No.2
Number of Pages:	13
Page Range:	pp. 258-270
Identification Number:	10.1039/c0sc00175a
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Wellcome Trust (London, England), National Science Foundation (U.S.) (NSF), JSSF, Edinburgh Protein Interaction Centre (EPIC), Oncosense Ltd.
Grant number:	20871069 (NSF), BK2008428 (JSSF)
URI:	http://wrap.warwick.ac.uk/id/eprint/5278

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