新型靶向拓扑异构酶I的抗肿瘤化合物库的设计、合成及生物活性研究

靶向Topo I的药物设计是目前重点研发的抗肿瘤药物之一。喜树碱类抗肿瘤药物由于其化学性质不稳定，毒性大，易产生耐药等缺陷，使得寻找靶向Topo I的非喜树碱类抗肿瘤新药，成为了近年来抗肿瘤药物研究的重要领域。.本研究课题是基于我们对以茚烯酮并异喹啉酮、苯并啡啶、骆驼宁碱及吲哚并咔唑为基本骨架的Topo I抑制剂在结构上的共性进行了研究和概括，结合对它们作用机制的初步认识，提出了平面结构单元与亲水侧链单元组合的化合物设计思路，并通过前期的实验研究验证了这一设计方法的可行性。本课题拟在这一设计思路及前期研究的工作基础上，综合采用优势结构理论、电子等排体替换、分子多样性及基于片段的先导化合物发现等药物分子设计理论，拟合成出含100-120个结构新颖的靶向Topo I的抗肿瘤化合物的化合物库，对其抗肿瘤活性、拓扑异构酶的抑制活性等进行构效关系研究，从中筛选出活性好的化合物进行进一步深入研究。

Today the search for novel TopoI-targeted scaffolds have drawn considerable research efforts in the hope of developing more effective antitumor drugs. As the only clinically available Topo I-targeted antitumor drugs, the CPTs suffer from many drawbacks such as chemically unstable, severe side effects, drug resistance and so on, which make the discovery of novel non-CPTs antitumor agents targeted to TopoI become a very active research field in recent years..Base on the structurally common feature of the TopoI-targeted compounds derivatived from Indenoisoquinolines, benzo[c]phenanthridines, Luotonins or Indolocarbazoles, and their basic mechanism of interaction with Topo I and DNA, we thought it would be a rational way to coin novel Topo I-targeted scaffolds by combination a flat planar motif with a hydrophilic moiety as side chain and the results in our recent studies really support the idea.These finding motivate us to put up with the research project to design and synthesize a 100 to 120 compounds library as potential anticancer-drug molecules targeted to the Topo I in the guides of the theories such as "privileged structure", "bio-isosterism alternation", "structure diversity", "fragment-based lead discovery" commonly used in drug-design, then to test the growth inhibitory effects of the synthesized compounds on selected tumor cell lines and to conduct a SAR/QSAR Study in the aim of identification several promising candidates for further research.