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    C-lysine conjugates as pH-controlled, light-activated reagents for double stranded DNA cleavage and associated methods
    3.
    发明授权
    C-lysine conjugates as pH-controlled, light-activated reagents for double stranded DNA cleavage and associated methods 有权
    作为用于双链DNA切割的pH控制的光活化试剂和相关方法的C-赖氨酸缀合物

    公开(公告)号：US08334403B1

    公开(公告)日：2012-12-18

    申请号：US12640877

    申请日：2009-12-17

    申请人： Igor Alabugin ,  Serguei Kovalenko ,  Wang Yong Yang ,  Kerry Gilmore ,  Boris Breiner

    发明人： Igor Alabugin ,  Serguei Kovalenko ,  Wang Yong Yang ,  Kerry Gilmore ,  Boris Breiner

    IPC分类号： C07C229/00 ,  C12Q1/68

    CPC分类号： C12N15/10 ,  A61K41/0042 ,  C12Q1/68 ,  C12Q2523/107 ,  C12Q2523/319 ,  C12Q2527/119

    摘要： Compounds and methods for double-stranded DNA cleavage of light-activated lysine conjugates are enhanced at the slightly acidic pH suitable for selective targeting of cancer cells by the presence of two amino groups of different basicities. The first amino group plays an auxiliary role 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. Protonation results in two synergetic effects which account for the increased DNA-cleaving ability at the lower pH: tighter binding to DNA at the lower pH; and 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. 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.

    摘要翻译： 光活化赖氨酸缀合物的双链DNA切割的化合物和方法在适于通过存在不同碱性的两个氨基的癌细胞的选择性靶向的微酸性pH下得到增强。 第一个氨基起增强对DNA的溶解度和亲和力的辅助作用，而位于光激活的DNA切割器旁边的第二个氨基在期望的pH阈值下进行质子化。 质子化导致两个协同作用，这说明在较低的pH值下增加的DNA切割能力：在较低pH下更紧密地结合DNA; 一旦发色团旁边的供体氨基被质子化，就消除了通过分子内电子转移而猝灭光致变色器的激发态的非生产途径。 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。