新哌啶并吲哚类TopoⅠ抑制剂的设计、合成、活性及初步机制研究

DNA topoisomerase Ⅰ（Topo Ⅰ）is a key enzyme that regulates the coiling of DNA during replication. Recent research has indicated that overexpression of Topo Ⅰplays an important role in various types of solid tumors formation. Targeting TopoⅠ has been considered as an efficient strategy to discover selective antitumor drugs. Funded by our former NSFC project (20802066), a new alkaloid with novel piperazino-indole scaffold was discovered for the first time using strictosidine synthase (STR1). Insight into how STR1 is capable of catalyzing the synthesis of this unique structure was gained using X-ray crystallography. The research results were published in Journal of the American Chemical Society (JACS) and were reported as spotlights by JACS. Based on this novel scaffold, a lead compound of Topo I inhibitor with multiple chiral centers was discovered, showing remarkable in vitro activity which is close to campothecin. Rational computer aided drug design upon it affords the objective piperazino-indole alkaloids which will be synthesized through a stereoselective and efficient chemo-enzymatic approach. Biological activities of compounds, such as enzyme inhibition, antitumor efficacy and potency, pharmacokinetics and pharmacodynamics,will be studied in vitro and in vivo. The X-ray crystallography of the complex between TopoⅠ and the synthesized inhibitors will delineate the biochemical mechanism of action. The aim of this project is the discovery of the potent candidates with improved therapeutic windows in preclinial studies, providing lead compounds with suitalbe druggability for clinical development.

DNA拓扑异构酶Ⅰ（TopoⅠ）通过控制DNA的拓扑状态，从而控制DNA复制过程，其在肿瘤组织中的表达远高于正常组织，是重要的抗肿瘤药物研究靶点。在上一国家基金青年项目（20802066）资助下，我们发现了异胡豆苷合成酶催化特异性底物首次得到哌啶并吲哚新结构母核的生物碱，并通过X-ray衍射阐明了其催化机制，研究工作发表于美国化学会志（JACS），并被其作为亮点进行了重点报道。在此基础上，我们发现了体外活性接近于喜树碱的Topo I抑制剂先导物- - 一个多环多手性中心的新哌啶并吲哚类生物碱。本项目将以此化合物为基础，通过计算机辅助药物设计，运用化学酶法立体选择性、快速地构建目标生物碱，经分子、细胞、动物三个层次的体内外活性筛选、药代动力学指标、构效关系及酶复合物结晶等多轮循环研究，以期发现可专利性强、成药性好的TopoⅠ抑制剂，并初步阐明其作用机制，为临床前药物研究提供新型抗肿瘤候选化合物。

DNA Topoisomerase I (Top1)是一类非常重要的酶，参与DNA的复制、转录、重组、修复等关键的核内过程。在肿瘤细胞中，Top1的含量及活性都远高于正常细胞，通过抑制Top1的活性，可以达到选择性抑制肿瘤细胞的快速增殖,进而杀死肿瘤细胞的目的。我们在发现的先导物的基础上，进行类药性合理设计，运用化学酶法立体选择性地构建了系列目标生物碱库，发现了体外对TopoⅠ及其高表达的肿瘤细胞的抑制活性的新生物碱，具有重要意义。同时在研究中还构建了基于裂环马钱子碱的新生物碱库，并合成了相关的类药库。

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