选择性识别G-四链体的新先导：结构优化、生物活性及作用机制研究

G- quadruplex targeting drugs is characterized by good tumor-cell-selective cytotoxicity, which is expected to develop novel high efficiency and low toxicity antitumor agents. A new series of molecule, 7a-7c for G-quadruplexes, which contains a crescent-shaped π-conjugated planar core, has been developed by our group recently. Such molecules have the properties to induce tumor cell apoptosis, as may provide the possibility to develop antitumor drugs. However，the poor water solubility restricts the pharmacokinetic properties. On the basis of our recent related studies, the project plan to modify the structure of the compounds aiming to improve the water solubility. Furthermore, the mechanism of tumor cell apoptosis by the compounds and the in vivo antitumor effects will be studied. Firstly, a series of derivatives will be synthesized by modifying the type and number of heteroatom on the aromatic ring as well as side-chains on the premise of assuring the compounds with crescent-shaped π-conjugated planar core. Secondly, the bonding strength, selectivity and stability of compounds with various G-quadruplex will be evaluated. Thirdly, the effect of compounds on the cell-uptake, cellular location, cellular selectivity and cellular morphology as well as inhibition of transcription and translation of proto oncogenes will be investigated. Forthly, the in vivo antitumor activity acute toxicity test will be evaluated. In a word, the implementation of this project will further the understandings of the tumor cell apoptosis by the compounds with crescent shape. It provide the reliable theoretical basis and technical guidance for the selection, development and application of antitumor drugs.

靶向特定G-四链体类化合物能够选择性杀伤癌细胞，有望开发成高效低毒的抗肿瘤药物。前期的预研工作发展了一类对正平行G-四链体具有良好选择性的新月形小分子化合物。该类化合物能够诱导肿瘤细胞发生凋亡，具有开发成抗肿瘤药物的潜在价值，但也存在难溶于水的缺点。基于此，本项目拟对该类化合物进行结构修饰以增强其水溶性，在此基础上，开展化合物诱导细胞凋亡的机理及体内抗肿瘤效果研究。具体为：1、保证整个分子呈新月形的前提下，改变芳环上杂原子的种类、数目及侧链，合成结构多样化的新型化合物；2、评价化合物与不同G-四链体的结合强度、选择性及稳定作用；3、研究化合物对细胞摄取、细胞内定位、选择性杀伤能力、对细胞形态的调控以及抑制原癌基因转录和翻译能力；4、对体内抗肿瘤活性及毒性进行评价。本项目的研究将进一步加深对新月形小分子诱导细胞调亡的理解，为抗肿瘤药物的筛选、开发及应用提供理论和技术指导。

G-四链体是一种特殊的DNA二级结构，基因转录的重要开关。靶向特定G-四链体类化合物对癌细胞和正常细胞具有良好的选择性，有望开发成高效低毒的抗肿瘤药物。在前期研究基础上，本项目系统开展了以下研究内容并取得了重要结果：（1）设计、合成了一系列新月形结构的衍生物并以此为基础成功构建了具有结构多样性的衍生物库。（2）对化合物库中的分子进行了一系列细胞内外的活性测试，包括衍生物对各种DNA（包括多种G-四链体DNA）的选择性、结合强度和稳定作用等；（3）研究化合物对细胞摄取、细胞内定位、选择性杀伤能力、对细胞形态的调控、对细胞凋亡诱导以及抑制原癌基因转录和翻译能力，获得了构效关系信息。为发展出高选择性、高效及低毒副作用的新抗癌药物提供了重要理论和实验依据。（4）发展的衍生物库中许多探针分子具有高灵敏度高特异性识别G-四链体，该探针同时对线粒体粘度具有良好的响应，发现了多个具有肿瘤诊疗一体化中的应用前景的分子。总的来说，本项目基本按原定计划开展了研究，完成了申请书中所制订的研究目标并取得了相应的研究成果，研究成果达到预期。