Issue 2, 2010

Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex

Abstract

The organometallic RuII arene complex [(η6-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 [1H, 1H] ROESY, NOESY, [1H, 15N] HSQC (using 15N-1), and [1H, 31P] 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 G3 and G6 (and G9, G12) and not G2 (or G8). Addition of a second mol equiv. of 1 gave di-ruthenated adducts (major sites G3/G6, G6/G9, G2/G6), and on reaction with a third mol equiv. tri-ruthenation (G2, G3/G6/G12).The NMR data are indicative of the coordinative binding of Ru-tha specifically to G3 and G6, together with penetrative intercalation of the bulky non-coordinated tha rings B and C of 1′, selectively between two base pairs G3/C10:C4/G9 and G6/C7:C5/G8. 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.

Graphical abstract: Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex

Supplementary files

Article information

Article type
Edge Article
Submitted
20 Feb 2010
Accepted
06 May 2010
First published
11 Jun 2010

Chem. Sci., 2010,1, 258-270

Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex

H. Liu, J. A. Parkinson, J. Bella, F. Wang and P. J. Sadler, Chem. Sci., 2010, 1, 258 DOI: 10.1039/C0SC00175A

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