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

Liu, Hong-Ke and Parkinson, John and Bella, Juraj and Wang, Fuyi and Sadler, Peter (2010) Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex. Chemical Science, 1 (2). pp. 258-270. ISSN 2041-6520

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The organometallic RuII arene complex [(eta6-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. Monointercalation 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.