基于Top1-Tdp1类两面针碱双靶点抑制剂多样性化合物库的设计、合成及抗肿瘤活性研究

肿瘤是危害人类健康的重大疾病，Top1抑制剂型化疗药物在治疗肿瘤具有不可取代的地位，但会产生骨髓抑制、呕吐和腹泻等副作用。研究发现，Tdp1可以特异性识别和修复由Top1介导的DNA损伤，抑制Tdp1的活性可以提高Top1抑制剂的抗癌治疗效果并降低毒性，因此，Top1-Tdp1双靶点抑制剂的研究极具吸引力。由于广西两面针主要成分氯化两面针碱具有优良的Top1抑制活性，本课题以Top1/Tdp1为靶点，基于前期本课题组发展的高价碘介导的钯催化偶联反应，利用多样性导向合成、药效团链接等策略，将类两面针碱骨架与Tdp1抑制剂含硫优势药效基团进行合理组合构建结构多样性的化合物库，采用MTT、凝胶电泳、荧光光谱、FRET等方法从生化水平和细胞水平对库中化合物进行抗肿瘤活性评价，并结合计算机辅助药物设计进行构效关系研究，为高效低毒类两面针碱双靶点抑制剂的开发应用提供理论和实验依据。

Cancer is one of the most serious diseases, and Top1 inhibitors are irreplaceable as chemotherapy drug, but which may produce serious side effects, including myelosuppression, vomiting and diarrhoea. Recent research has showed that Tdp1 can specifically recognize and repair Top1-mediated DNA damage. Inhibiting the activity of Tdp1 could improve the anticancer efficacy of Top1 inhibitors and reduce their toxicity. Therefore, the research of dual target inhibitors of Top1-Tdp1 is very attractive. This project mainly focuses on the privileged skeletons like Nitidine chloride from Guangxi characteristic medicinal materials Zanthoxylum nitidum (Roxb.) DC, which exhibit remarkable Top1 inhibition activities．Based on our previous study results of Palladium-catalyzed coupling reaction in the presence of hypervalent iodine reagents, this project will be construct novel molecular hybrids libraries of Nitidine-like skeleton containing the advantages of the pharmacophore active fragments of Tdp1 inhibitors with sulfur-containing moiety targeting Top1/Tdp1 by employing diversity-oriented synthesis (DOS), and pharmacophore-linked methods. The antitumor activities will be explored by methods of MTT, Gel electrophoresis, Fluorescence and FRET at biochemical and cellular levels, aiming to clarify the relationship among Top1/Tdp1 and their antitumor activity. The structure-activity relationship will be studied with computer aided drug design. This research may provide theoretical and experimental datas for further exploiting of new higher effective and lower toxic Nitidine-like lead compounds as Dual target inhibitor.