含卓酮环的多环稠喹啉骨架的构建.苯并[4,5]卓酮并[1,2-b]喹啉类衍生物合成及抗肿瘤活性研究

N-Heterocycle-fused tropone skeleton and planar polycyclic-fused quinoline system are pharmaceutically significant pharmacophores, and widely used as molecular templates for the design and synthesis of bioactive compounds and drugs. However, incorporation of the tropone nucleus into the planar polycyclic-fused quinoline systems leading to a novel hybrid polycyclic tropone-fused quinoline system has not been achieved so far, probably due to the fact that tropone derivatives are scarce in nature and limited information is available. Thus, the aim of the present work was to develop a simple and elegant synthetic strategy to incorporate the two moieties into a molecular frame work by fused forms, as possible drug-like candidates for pharmacological studies. The designed synthetic plan involved the one-pot synthesis of (E)-2-(aryl/hetarylvinyl)quinoline-3-carboxylic acids using ethyl 2-halomethylquinoline-3-carboxylate as starting materials. Subsequently, the resulting precursors underwent the intramolecular Friedel-Crafts acylation reaction resulting the formation of seven-member tropone ring by the generation of a new C-C bond between 3-carboxylic acid and 2-aryl/hetarylvinyl. Through the synthetic strategy, structurally novel benzo[4,5]tropono[1,2-b]quinoline derivatives could be obtained and their anti-tumor activity could be evaluated.

氮杂环并卓酮结构和共平面多环稠喹啉体系均可以被用作良好的药效团进行药物活性分子设计与合成。但如何将卓酮环稠合到多环稠喹啉体系形成同时符合这两种药效基结构特点的新骨架结构目前仍未实现，可能由于卓酮在自然界存在比较罕见，关注度不高。本项目旨在通过设计一种简单有效的合成策略，实现这两种活性结构以共平面稠合形式构筑于同一分子，突破现有所采用多环稠喹啉体系作为药效基进行药物分子设计与合成的局限性。该策略以2-卤甲基喹啉-3-甲酸乙酯为原料依次进行Arbuzov反应、Horner-Emmons反应和酯水解反应，经“一锅法”构建2-芳（杂）乙烯基喹啉-3-羧酸结构体系，从而利用其3位羧基与乙烯基的芳杂环发生分子内的Friedel-Crafts酰基化反应构建七元卓酮环，这样卓酮环就稠合到喹啉骨架上。利用这一策略合成新颖的苯并[4,5]卓酮并[1,2-b]喹啉类衍生物，研究其抗肿瘤活性。

氮杂环并卓酮结构和共平面多环稠喹啉体系均可以被用作良好的药效团进行药物活性分子设计与合成。本项研究以2-氯甲基喹啉-3-甲酸乙酯为底物成功构建了一系列结构新颖的喹啉并卓酮类化合物。反应物通过连续的与亚磷酸三乙酯的Arbuzov反应、与芳（杂）芳醛的Horner-Emmons反应和3-位酯基的水解反应，“三步一锅法”的高收率合成了2-芳基（杂芳基）乙烯基喹啉-3-羧酸类化合物。该合成方法不受反应物取代基效应的影响，具有很好的普适性，而且具有实验操作和后处理简单、所需试剂廉价易得、产品收率高等优点。对其分子内的Friedel-Crafts酰基化反应研究发现：在多聚磷酸（PPA）或Eaton试剂的作用，未取代的或供电子基团取代的2-芳基乙烯基喹啉-3-羧酸能够顺利发生环化反应制得想要的芳基并[4,5]卓酮并[1,2-b]喹啉，而含强吸电子基团或2-杂芳基乙烯基取代的喹啉-3-羧酸或生成了六元内酯环或得到较为复杂，难以分离混合物。从目标化合物的抗A549和HT-29肿瘤活性测试结果发现，含有卤素官能团的化合物表现出很好的抗肿瘤活性，而对于未取代或含有供电子基团的，肿瘤抑制活性较低。通过本项目的研究，不仅丰富了非苯芳烃卓酮化学，扩展了卓酮类化合物的分子多样性，而且也为该领域抗肿瘤活性药物分子的研究提供了崭新的分子结构模型，具有重要的学术价值和应用前景。