期刊
CHEMICAL SCIENCE
卷 1, 期 2, 页码 258-270出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c0sc00175a
关键词
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资金
- Wellcome Trust
- NSF [20871069]
- JSSF [BK2008428]
- Edinburgh Protein Interaction Centre
- Oncosense Ltd
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.
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