Inosine Can Increase DNA's Susceptibility to Photo-oxidation by a RuII Complex due to Structural Change in the Minor Groove
Inosine Can Increase DNA's Susceptibility to Photo-oxidation by a RuII Complex due to Structural Change in the Minor Groove
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DOI：
10.1002/chem.201701447
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发表时间：
2017-08-01
影响因子：
4.3
通讯作者：
Kelly, John M.
中科院分区：
文献类型：
--
作者：
Keane, Paraic M.;Hall, James P.;Kelly, John M.
开发DNA靶向光治疗药物的关键是确定药物的光活性及其对靶序列的结合偏好之间的相互作用。对于光氧化λ-[ Ru（TAP）（2）（dppz）]（2+）（λ-1）（dppz=二吡啶并吩嗪）配合物与d{T（1）C（2）G（3）G（4）C（5）G（6）C（7）C（8）G（9）A（10）}（2）（G9）或d{TCGGCGCCIA}（2）（I9）结合，X-射线晶体结构表明dppz插层在T1 C2末端; G（9）A（10）阶跃或T1 C2; I（9）A（10）阶跃。因此，G（9）核碱基被肌苷取代不影响固体状态下的嵌入，尽管I-9使dppz更深地插入。在溶液中，它被发现的鸟嘌呤光氧化的程度，和背电子转移的速率，如确定的皮秒和纳秒时间分辨红外和瞬态可见吸收光谱，是在I9中增强，尽管它含有较少的氧化肌苷。这归因于由于不存在NH 2基团而在小沟中结合的性质。发现d{TTGGCGCCAA}（2）（A9）的晶体中具有类似的行为和相同的结合位点。在溶液中，我们提出嵌入分别发生在C（2）G（3）; C8 I9或T（2）G（3）; C（8）A（9）步骤，其中G（3）可能是光氧化的目标。这证明了小沟的变化（在这种情况下去除NH 2基团）如何促进RuIIdppz复合物的结合，从而影响在这些位点发生的任何敏化反应。δ对映异构体与I-9结合时没有类似的光氧化增强作用。
Key to the development of DNA-targeting photo-therapeutic drugs is determining the interplay between the photoactivity of the drug and its binding preference for a target sequence. For the photo-oxidising lambda-[ Ru( TAP)(2)(dppz)](2+) (Lambda-1) (dppz= dipyridophenazine) complex bound to either d{T(1)C(2)G(3)G(4)C(5)G(6)C(7)C(8)G(9)A(10)}(2) (G9) or d{TCGGCGCCIA}(2) (I9), the X-ray crystal structures show the dppz intercalated at the terminal T1C2; G(9)A(10) step or T1C2; I(9)A(10) step. Thus substitution of the G(9) nucleobase by inosine does not affect intercalation in the solid state although with I-9 the dppz is more deeply inserted. In solution it is found that the extent of guanine photo-oxidation, and the rate of back electron-transfer, as determined by pico-and nanosecond time-resolved infrared and transient visible absorption spec-troscopy, is enhanced in I9, despite it containing the less oxidisable inosine. This is attributed to the nature of the binding in the minor groove due to the absence of an NH2 group. Similar behaviour and the same binding site in the crystal are found for d{TTGGCGCCAA}(2) (A9). In solution, we propose that intercalation occurs at the C(2)G(3); C8I9 or T(2)G(3); C(8)A(9) steps, respectively, with G(3) the likely target for photo-oxidation. This demonstrates how changes in the minor groove (in this case removal of an NH2 group) can facilitate binding of RuIIdppz complexes and hence influence any sensitised reactions occurring at these sites. No similar enhancement of photooxidation on binding to I-9 is found for the delta enantiomer.