苯并[de][1,6]萘啶酮类新型ChK1抑制剂的设计合成和药理活性研究

Benzo[de][1,6]naphthyridinones are a class of bioactive alkaloids and isolated from marine sponge from South China Sea, which exhibited good inhibition activity to checkpoint kinase 1 (ChK1) and significantly reduced tumor stem cells survival in vitro in combination with chemotherapy drugs. The efficient total synthesis of the natural products has been completed via a novel palladium-catalyzed reductive cyclization strategy and a series of derivatives have been synthesized in our previous investigation. The structure-activity relationship studies indicated that the alkylamino substituents involved in the intramolecular hydrogen bond played a vital role in determining their inhibition activity to ChK1. The compounds with longer carbon chain of alkylamino group or more substituents on the aromatic rings displayed more potent inhibition against ChK1. .Based on the results of molecular docking and pharmacological experiments, our attention will be focused on the modification of benzo[de][1,6]naphthyridinone molecular in the present project. 60-80 well-designed derivatives are planned to be synthesized and studied in depth the influence of the length and type of the alkylamino group, character of the functional groups on the aromatic core and installation of substituents on different positions of the aromatic core on inhibition activity to ChK1 and cytotoxicities. The purpose of this project is to elucidate the structure-activity relationship of inhibition activity to ChK1 in detail and examine the anti-tumor stem cell activity in combination with chemotherapy drugs, which will finally discover and develop novel ChK1 inhibitors.

苯并[de][1,6]萘啶酮ABN-3是申请人课题组从海绵中分离得到的活性天然产物，对细胞周期检查点激酶（ChK1）有良好的抑制作用，能够显著增强肿瘤干细胞对化疗药物的敏感性。申请人采用钯催化还原环化反应策略完成了该天然产物及其衍生物的高效全合成。构效关系研究发现烷胺取代基是该类化合物ChK1抑制作用的活性基团，延长烷胺基碳链长度和增加基团内芳香环的取代基数目都能够提高化合物的ChK1抑制活性。.结合计算机辅助药物设计和药理学实验结果，本项目拟对前期筛选的化合物进一步优化，通过考察化合物烷胺取代基的类型和长度、母核取代基团性质以及在多个位点引入官能团等方式，设计合成60-80个多类苯并[de][1,6]萘啶酮衍生物，评价其ChK1抑制活性和细胞毒性，筛选高效低毒的化合物进而系统开展其联合化疗药物抗肿瘤干细胞活性研究，揭示其抗肿瘤构效关系和作用机制，最终获得更具开发潜力的新型ChK1抑制剂。

稠环类海洋生物碱是一类具有广泛生物活性的海洋天然产物。其中， 烷胺基取代的苯并[de][1,6]萘啶酮类化合物能与细胞周期检查点激酶（ChK1）特异性结合，从而提高顺铂等化疗药物对肿瘤干细胞的抑制活性，是一类潜在的肿瘤干细胞化疗增敏药物。由于该类生物碱在海洋生物体内含量极其稀少，限制了其构效关系和作用机制的系统性研究。本项目通过发展过渡金属催化的还原环化反应和Vilsmeier-Haack反应等关环反应，对苯并萘啶酮类、吲哚联异喹啉类和吡啶并吖啶类海洋生物碱的合成进行了系统研究，成功构建了多类海洋稠环生物碱的全合成路线，从而对不同种类稠环生物碱的ChK1抑制活性和抗肿瘤活性进行深入研究。.本项目通过采用计算机辅助药物设计技术，对多类海洋生物碱与ChK1激酶蛋白进行分子对接实验，并根据其结果和全合成方案设计并合成了约100个多种类型海洋稠环生物碱，并对其抗肿瘤活性和化疗增敏作用进行了系统性筛选评价。其中对碳8位烷胺基取代的苯并[de][1,6]萘啶酮的结构优化得到多肽取代的苯并萘啶酮ANB-52，能够显著增加化疗药物对肺癌干细胞的杀伤作用；碳3位和碳8位芳香环双取代的苯并萘啶BND-34，对血液瘤具有显著的抑制作用；吡啶并吖啶类生物碱PYN-22能够在低光密度条件下，高效率产生ROS从而对肿瘤细胞具有光毒性。通过本课题的实施，系统性发展了苯并萘啶等多种海洋稠环先物碱的合成与结构优化方法，而且为肿瘤干细胞化疗增敏剂的药物开发奠定基础。

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