Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex
Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex
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DOI：
10.1039/c0sc00175a
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发表时间：
2010-01-01
期刊：
影响因子：
8.4
通讯作者：
Sadler, Peter J.
中科院分区：
文献类型：
--
作者：
Liu, Hong-Ke;Parkinson, John A.;Sadler, Peter J.
有机金属Ru-II芳烃配合物[（eta（6）-tha）Ru（en）Cl]（+）（1），其中tha四氢蒽和en =乙二胺，对癌细胞具有强效细胞毒性。我们已经使用了HPLC，ESI-MS，1D-和2D-NMR的组合，包括[H-1，H-1] ROESY，NOESY，[H-1，N-15] HSQC（使用N-15-1）和[H-1，P-31]实验来阐明THA的非芳香族大环在与DNA六聚体d（CGGCCG）加合物中的作用，因为DNA是该药物的潜在靶点。1与单链d（CGGCCG）的反应在三个G碱基中的每一个上引起双链化，而双链体d（CGGCCG）（2）与1 mol equiv. 1导致了G（3）和G（6）（以及G（9），G（12））的排它性，而不是G（2）（或G（8））.加入第二摩尔当量。1的反应生成二烯化加合物（主要位点G（3）/G（6），G（6）/G（9），G（2）/G（6）），与第三mol当量的1反应生成二烯化加合物（主要位点G（3）/G（6））。三取代（G（2），G（3）/G（6）/G（12））。NMR数据表明Ru-tha特异性地与G（3）和G（6）配位结合，以及1 '的大体积非配位的tha环B和C选择性地在两个碱基对G（3）/C-10：C-4/G（9）和G（6）/C-7：C-5/G（8）之间渗透插入。通过tha在GpC基础台阶处的嵌入与在GpG基础台阶处的嵌入相比具有较低的能量损失，从而允许容纳tha。THA的单插层降低了en-NH与GO 6之间的氢键强度。与顺铂相比，Ru-tha与GN 7的协调结合诱导的结构扭曲的这些差异可能导致作用机制的差异，包括金属化病变的蛋白质识别和缺乏交叉耐药性。
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.