C-lysine conjugates: pH-controlled light-activated reagents for efficient double-stranded DNA cleavage with implications for cancer therapy.
C-lysine conjugates: pH-controlled light-activated reagents for efficient double-stranded DNA cleavage with implications for cancer therapy.
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DOI：
10.1021/ja902140m
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发表时间：
2009-08-19
影响因子：
15
通讯作者：
Alabugin IV
中科院分区：
文献类型：
--
作者：
Yang WY;Breiner B;Kovalenko SV;Ben C;Singh M;LeGrand SN;Sang QX;Strouse GF;Copland JA;Alabugin IV
光活化赖氨酸缀合物的双链DNA切割在适于选择性靶向癌细胞的微酸性pH（<7）下强烈增强。这种增强源于存在两个不同碱度的氨基。第一个氨基通过增强溶解度和对DNA的亲和力而起辅助作用，而位于光激活的DNA切割剂旁边的第二个氨基在所需的pH阈值下经历质子化。这种质子化导致两种协同效应，这两种协同效应解释了在较低pH下增加的DNA切割能力。首先，赖氨酸缀合物在较低pH下显示出与DNA更紧密的结合，这与预期的两个带正电荷的铵基团与带负电荷的DNA磷酸骨架之间的更高程度的相互作用一致。其次，一旦紧邻发色团的供体氨基被质子化，则通过分子内电子转移猝灭光切割剂的激发态的非生产性途径被消除。在存在用于扩散自由基的陷阱的情况下的实验表明，活性氧物质在较低pH下对DNA切割的机制没有显著贡献，这表明在这些条件下与DNA的结合更紧密。这一特征是有价值的，不仅因为许多实体瘤是缺氧的，而且因为不依赖于扩散物质的裂解更局部化和有效。序列选择性实验表明PET和碱基烷基化的组合作为所观察到的DNA损伤的化学基础。这些分子用于癌症光疗的效用通过光活化后五种缀合物对癌细胞系的毒性急剧增加来证实。
Double-stranded DNA cleavage of light-activated lysine conjugates is strongly enhanced at the slightly acidic pH (<7) suitable for selective targeting of cancer cells. This enhancement stems from the presence of two amino groups of different basicities. The first amino group plays an auxiliary role by enhancing solubility and affinity to DNA whereas the second amino group which is positioned next to the light-activated DNA-cleaver undergoes protonation at the desired pH threshold. This protonation results in two synergetic effects which account for the increased DNA-cleaving ability at the lower pH. First, lysine conjugates show tighter binding to DNA at the lower pH, which is consistent with the anticipated higher degree of interaction between two positively charged ammonium groups with the negatively charged phosphate backbone of DNA. Second, the unproductive pathway which quenches the excited state of the photocleaver through intramolecular electron transfer is eliminated once the donor amino group next to the chromophore is protonated. Experiments in the presence of traps for diffusing radicals show that reactive oxygen species do not contribute significantly to the mechanism of DNA cleavage at the lower pH, which is indicative of tighter binding to DNA under these conditions. This feature is valuable not only because many solid tumors are hypoxic but also because cleavage which does not depend on diffusing species is more localized and efficient. Sequence-selectivity experiments suggest combination of PET and base alkylation as the chemical basis for the observed DNA-damage. The utility of these molecules for phototherapy of cancer is confirmed by the drastic increase in toxicity of five conjugates against cancer cell lines upon photoactivation.
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影响因子：
14.9
作者：
Adhikary, A;Buschmann, V;Sauer, M
通讯作者：
Sauer, M
影响因子：
15
作者：
ARMITAGE, B;YU, CJ;SCHUSTER, GB
通讯作者：
SCHUSTER, GB
DOI：
10.1073/pnas.97.14.7814
发表时间：
2000-07-05
影响因子：
11.1
作者：
Baliga, R;Crothers, DM
通讯作者：
Crothers, DM
DOI：
10.1016/j.bbagen.2007.03.001
发表时间：
2007-07-01
影响因子：
3
作者：
Bhadra, Kakah;Maiti, Motilal;Kumar, Gopinatha Suresh
通讯作者：
Kumar, Gopinatha Suresh
影响因子：
4.4
作者：
Ahmad, J;Ashok, BT;Ali, R
通讯作者：
Ali, R