吲哚并喹唑啉类天然产物衍生物的合成与抗肿瘤活性研究

It is a great need for development of antitumor drugs to save human being and also is much in demand of reduce the pain of the patient. Natural active substances have contributed significantly to the drug discovery, and the synthesis and biological activity research of their derivatives have also play an important role in all kinds of new drug discoveries, it is also the main source of new lead compounds research. The natural products based on the skeleton of indoloquinazoline have attracted more and more attention because of their unique structure and broad spectrum biological activities, but the synthetic method of indoloquinazolines has been too unique to have structure variability, which has hindered their research and applications. This project is based on the active natural products Hinckdentine A,Phaitanthrin B, D, E and according to the principle of combination of bioactive sbustructures and bioisosterism to modify the natural products structure. And then through the introduction of high activity substituents at different sites to improve the pharmacological activities. In this project, we will use the strategies of continuous multicomponent reaction to synthesis series of indoloquinazoline natural product derivatives, and through the antitumor activity tests and structure-activity relationship research to further optimize the structure of compounds and to understand the relationship between pharmacophore and the structure, and finally find new antitumor lead compounds. The completion of the project will provide new methods for the synthesis of natural products derivatives based on the skeleton of indoloquinazoline and accelerate the development of new antitumor drugs.

研发抗肿瘤新药是挽救人类，减少病痛的迫切需求，天然活性物质是新药研发的先导物，其衍生物的合成与生物活性研究在各类新药研发中都具有重要的地位，是发现新型先导药物的重要源泉。吲哚并喹唑啉类天然产物因结构独特、生物活性广谱而备受化学家的关注，然而该类化合物的制备方法单一，结构缺少变化，限制了其开发应用。在前期多组分串联反应研究的基础上，本项目拟以活性天然产物Hinckdentine A及Phaitanthrin B、D、E为模板，根据活性叠加及电子等排原理，改造天然产物结构，并在不同位点引入高活性取代基，提高其药理活性；拟采用连续的多组分-串联反应策略来高效合成系列该类天然产物衍生物，经结构变化和抗肿瘤活性测试，进一步研究其构效关系，优化化合物类型，准确把握药物活性位点，并最终发现新型抗肿瘤先导化合物。本项目的完成将为吲哚并喹唑啉类天然产物衍生物的合成提供新方法，并加速该类抗肿瘤新药研发过程。

抗肿瘤新药的研究开发是挽救人类，减少病痛的迫切需求。天然活性物质是新药研发的先导物，且其衍生物的合成与生物活性研究在各类新药研发中都具有重要的地位，是发现新型先导药物的重要源泉。吲哚并喹唑啉类天然产物因结构独特、生物活性广谱而备受化学家的关注，关于含有吲哚并喹唑啉母体环系天然产物的研究，近几年不断有文献报道，本项目以吲哚并喹唑啉类天然产物衍生物的合成与抗肿瘤活性研究为指导思想，主要进行了以下工作：（1）以吲哚并喹唑啉类天然产物骨架为母体，依据活性叠加和电子等排原理，在不同位点引入高活性取代基，采用连续的多组分-串联反应策略合成了75个天然产物Hinckdentine A及Phaitanthrin B、D、E类似物，所有化合物的结构均经1HNMR、13CNMR和lcms确认。（2）对所有合成的新化合物进行了抗肿瘤活性测试，结果表明，虽经结构修饰及取代基变换，该类天然产物类似物的抗肿瘤活性提高不明显，均低于对照药物5-氟尿嘧啶。（3）在探索吲哚并喹唑啉类天然产物母体结构的制备过程中，结合多组分合成策略的优越性，我们还建立了连续的多组分-串联反应在合成其他含氮杂环化合物中的新方法，设计合成了一系列杂环类化合物，包括多取代的吡咯并[3,2-d]嘧啶、喹啉、苯并呋喃并[2,3-c]喹啉、吡咯并[3,4-c]喹啉等。