【作者】 郭威；

【导师】 孙斌；

【作者基本信息】 山东大学 ， 生物与医药（专业学位）， 2024， 硕士

【摘要】 癌症的全球发病率和死亡率每年持续上升,对人类生命健康构成重大威胁。针对癌症的治疗,药物治疗方法目前已成为应用最广泛、使用频率最高的治疗方法之一。天然产物凭借其复杂且独特的骨架结构在新药研发过程中发挥了重要作用,已有大量的上市药物直接或间接地来源于天然产物。双联苄类化合物是广泛存在于植物界内的天然产物,因其结构多样性,在抗肿瘤、微管蛋白抑制、抗病毒、抗炎、抗蛇毒、抗真菌、抗氧化剂和神经保护等方面表现出了良好的生物学活性。在前期研究基础之上,本论文对地钱素B进行了全合成研究。经过逆合成分析,设计了一条全合成线路,首次实现了对地钱素B的全合成。后又对地钱素B通过烷基化和胺甲基化修饰引入含氮基团,共制备了 10个含氮衍生物。应用MTT法测定衍生物对H460(人大细胞肺癌细胞)、H460-RT(人大细胞抗肺癌耐药株细胞)、A549(肺癌人类肺泡基底上皮细胞)、A549-Tax(肺腺癌紫杉醇耐药株细胞)、PC3(人前列腺癌细胞)和MCF-7(人乳腺癌细胞)的抗肿瘤活性,结果表明,酚羟基烷基化修饰的衍生物具有良好的抗肿瘤活性。其中化合物18d的半数抑制浓度IC50值为0.48 μM～0.86μM。通过上一章对地钱素B衍生化抗肿瘤活性结果,利用骨架跃迁策略,对地钱素B骨架进行简化,将含氮基团以哌嗪环和含氮脂肪链的方式引入骨架中,设计制备了 14个新骨架化合物。经过体外抗肿瘤活性评价,得到了抗肿瘤活性最好的化合物BN4,IC50值为1.39 μM～2.45 μM,与地钱素B相比活性提高了 4倍以上。构效关系总结为:引入含氮脂肪链整体效果好于引入哌嗪环片段;B环醚键的位置应在联苄的间位;脂肪氮链上仲胺的效果好于叔胺和季胺。为下一步作用机制研究和创新型药物研发奠定了基础。更多还原

【Abstract】 The global incidence and mortality of cancer continue to rise every year,posing a major threat to human life and health.For the treatment of cancer,drug therapy has become one of the most widely used and frequently used therapeutic methods.Natural products have played an important role in the development of new drugs due to their complex and unique skeleton structure,and a large number of marketed drugs have been derived directly or indirectly from natural products.Bibenzyl compounds are natural products widely existing in plants.Due to their structural diversity,bibenzyl compounds have shown good biological activities in anti-tumor,tubulin inhibition,antiviral,antiinflammatory,antivenom,antifungal,antioxidant and neuroprotective aspects.Building on previous research,this paper presents a comprehensive study on the total Synthesis of marchantin B Through retrosynthetic analysis,a novel synthetic route was designed and successfully implemented,achieving the first total Synthesis of marchantin B.Subsequently,ten nitrogen-containing derivatives were synthesized by introducing nitrogen-containing groups into marchantin B via alkylation and aminomethylation modifications.The antitumor activities of the derivatives against human large cell lung cancer cells(H460),human large cell lung cancer drug resistant strains(H460-RT),A549(human non-small cell lung cancer cells),lung adenocarcinoma paclitaxel-resistant cells(A549-Tax),human prostate cancer cells(PC3),and human breast cancer cells(MCF-7)were evaluated using the MTT method.The results showed that the antitumor activities of the alkylated derivatives were all significantly improved.Among them,the half-maximal inhibitory concentration(IC50)values of compound 18d were 0.48 μM to 0.86 μM.Based on the results of derivatization and anti-tumor activity of Marchantin B in the previous chapter,the framework of marchantin B was simplified using scaffold hopping strategy.Nitrogen containing groups were introduced into the framework in the form of piperazine rings and nitrogen-containing fatty chains,and 14 new framework compounds were designed and prepared.In vitroantitumor activity evaluation showed that compound BN4 had the best antitumor activity,with IC50 values of 1.39 μM to 2.45 μM,which was more than 4 times higher than that of marchantin B.The structure-activity relationship was summarized as follows:the overall effect of introducing nitrogen-containing aliphatic chains was better than that of introducing piperazine ring fragments;the position of the B-ring ether bond should be at the meta position of the Bibenzyl;and the effect of secondary amines on the aliphatic nitrogen chain was better than that of primary and tertiary amines.This study laid the foundation for further research on the mechanism of action and the development of innovative drugs.更多还原