选择性识别人端粒双倍体G-四链体的双平面链状分子的合成及调控生物活性研究

It is known that telomere terminal overhang is 100-200 nt and can form higher-order G-quadruplex structures that consist of consecutive G-quadruplex units connected by TTA linkers. Therefore, considerable interests have been attracted in the rational design of small organic molecules that are capable of targeting dimeric or multimeric G-quadruplex units and consequently inhibiting telomerase activity and cancer cell proliferation. However, most studies to date have been confined to ligand binding to G-quadruplex monomers (typically 21-26 nt) of human telomere. Furthermore, there are few reports on ligand binding to dimeric or multimeric G-quadruplex units. In addition, two reported modes of ligand binding to dimeric or multimeric G-quadruplex units are subjected to low stability and selectivity of dimeric over multimeric G-quadruplex units. In this project, a series of bipyrrole-polyamide-tethered dimeric berberine and nitrogen-containing heterocyclic compounds will be synthesized with the aim to improve the stability and selectivity of dimeric G-quadruplex units. Specifically, the two planar structures may accumulate two adjacent G-four split planes, whereas the bipyrrole-polyamide subunits selectively recognize the TTA linker. This new binding mode will be investigated by means of UV-Vis, fluorescence, CD, NMR and molecular modeling. The structure-activity relationship will be clarified. The telomeric activity and cancer cell proliferation will be also studied. This project is expected to provide valuable guidance for the rational design of antitumor drugs targeting dimeric G-quadruplex units.

人端粒末端悬突有100-200 nt的端粒DNA，可形成TTA碱基序列连接的双倍体或多倍体G-四链体，以稳定的双倍体或多倍体G-四链体作为抗肿瘤药物的靶点，开展抑制端粒酶活性及癌细胞增殖的药物研发，具有非常重大的意义。目前研究多集中稳定由21-26 nt的短链人端粒DNA形成的单倍体G-四链体，而双倍体或多倍体G-四链体的选择性识别研究很少，且报道的结合模式在选择性识别和稳定DNA方面均存在不足。据此本项目依据双倍体G-四链体的结构特点设计了一种新的结合模式，合成双吡咯聚酰胺两端连接小檗碱衍生物或含氮杂环双喹啉衍生物，通过两端平面结构及双吡咯聚酰胺链，实现对相邻G-四分体平面及TTA碱基的一一对应识别，以增强选择性识别和稳定性，以紫外、荧光、CD谱、核磁及分子模拟等研究结合模式，阐明构效关系；研究对端粒酶活性及癌细胞增殖的影响。这为以双倍体G-四链体为靶点的药物设计提供更有价值的指导意义。

人端粒末端悬突有100-200 nt的端粒DNA，可形成TTA碱基序列连接的双倍体或多倍体G-四链体，以稳定的双倍体或多倍体G-四链体作为抗肿瘤药物的靶点，开展选择性更强毒性更低的抑制端粒酶活性及癌细胞增殖的药物研发，具有非常重大的意义。目前研究多集中稳定由21-26 nt的短链人端粒DNA形成的单倍体G-四链体，而双倍体或多倍体G-四链体的选择性结合和识别研究很少。据此本项目依据双倍体G-四链体的结构特点，合成不同聚醚链长连接的双小檗碱衍生物、双希夫碱金属镍配合物及双喹啉二聚体衍生物，通过两端平面结构及合适的聚醚链长，实现对双倍体G－四链体DNA的选择性识别，以紫外、荧光、CD谱、CD-mleting、聚丙烯酰胺凝胶电泳等研究结合能力和结合选择性，探讨结合模式，阐明构效关系；研究对端粒酶抑制活性和癌细胞增殖的影响。该研究得到了以聚醚－小檗碱二聚体衍生物、聚醚－席夫碱双核镍金属配合物和聚醚连接的双喹啉衍生物为代表的优良的双倍体G－四链体结合剂，和以聚醚－小檗碱二聚体衍生物为代表的双倍体G－四链体荧光探针，这为以多倍体G-四链体为靶点的疾病检测和药物设计提供了更有价值的指导意义。

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