Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complexElectronic supplementary information (ESI) available: Reactions of II with 15N-1. HPLC, HPLC-ESI-MS, NMR and pH measurements, Tables S1-S7 and Figs. S1-S7. See DOI: 10.1039/c0sc00175a

• Main Authors: Liu, Hong-Ke, Parkinson, John A, Bella, Juraj, Wang, Fuyi, Sadler, Peter J
• Format: Article
• Language: English
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c0sc00175a

The organometallic Ru II arene complex [(η 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 [ 1 H, 1 H] ROESY, NOESY, [ 1 H, 15 N] HSQC (using 15 N- 1 ), and [ 1 H, 31 P] 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. Studies of the reactions of a Ru II tetrahydroanthracene anticancer complex with DNA by 2D NMR and HPLC-MS reveal penetrative DNA intercalation and G-base selectivity.