【作者】 李健；

【导师】 商士斌；

【作者基本信息】 中国林业科学研究院 ， 林产化学加工工程， 2012， 博士

【摘要】 松香作为我国一种重要的天然可再生资源，具有广泛的生物活性。丙烯海松酸是松香发生D-A加成反应的深加工产品，由于其独特的结构和反应活性，越来越受到广泛关注。本文以丙烯海松酸为原料，经酯化、SWERN还原、硫代、溴代等反应，制备了丙烯海松酰胺、丙烯海松肟酯、丙烯海松希夫碱、丙烯海松酰腙、丙烯海松酰基硫脲、丙烯海松噻二唑六大类共53个新化合物；采用IR、NMR、元素分析、质谱等手段对所合成的化合物进行结构表征，确定了化合物的结构；对合成的化合物分别进行了抑菌和体外抗肿瘤活性研究，并建立了抑菌活性定量构效关系模型，以期指导下一步生物活性化合物的合成。采用滤纸片法对丙烯海松酰胺、丙烯海松肟酯、丙烯海松希夫碱、丙烯海松酰腙、丙烯海松酰基硫脲、丙烯海松噻二唑六大类化合物进行了抑菌性能研究。受试菌种选择具有代表性的金黄色葡萄球菌（革兰氏阳性菌）和大肠杆菌（革兰氏阴性菌）。研究结果表明所合成的化合物对金黄色葡萄球菌大肠杆菌和大肠杆菌具有一定的抑制效果。其中丙烯海松肟酯类化合物：3c（12.17mm）、3d（10.00mm）、3f（10.33mm）；丙烯海松希夫碱类化合物：4a（15.70mm）、4b（17.00mm）和4c（16.70mm）；丙烯海松酰腙类化合物：5a（10.00mm）、5c（10.00mm）；丙烯海松酰基硫脲类化合物：6f（10.00mm）；丙烯海松噻二唑类化合物：7f（10.66mm）对大肠杆菌具有较好的抑菌活性，表现在256μg/mL浓度下，抑菌环直径比市售杀菌剂新洁尔灭（7.90mm）的抑菌环直径要大，这些化合物可以作为抑菌剂进一步分离提纯和开发。采用MTT比色法对丙烯海松酰胺、丙烯海松肟酯、丙烯海松希夫碱、丙烯海松酰腙、丙烯海松酰基硫脲、丙烯海松噻二唑六大类化合物进行了体外抗肿瘤活性研究。受试细胞以处于对数生长期的细胞（人非小细胞肺癌NCI-H460细胞、人肝癌SMMC-7721细胞、人乳腺癌MCF-7细胞）为受试细胞，根据改进寇氏法计算半数抑制浓度(IC₅₀)，当IC₅₀<10μg/mL时，判断该化合物具有体外抗肿瘤活性。研究结果表明所合成的化合物对NCI-H460细胞、SMMC-7721细胞和MCF-7细胞具有一定的抑制作用。其中丙烯海松肟酯类化合物3k对NCI-H460细胞、SMMC-7721细胞、MCF-7细胞的半数抑制浓度IC₅₀均接近于10μg/mL，显示对肿瘤细胞具有一定的杀伤抑制作用，同时对肿瘤细胞的抑制率随化合物的浓度增加而呈S型曲线变化；丙烯海松希夫碱衍生物对体外培养的NCI-H460细胞、SMMC-7721细胞、MCF-7细胞均有较好的抑制作用，表现在他们的半数抑制浓度IC₅₀均接近或小于10μg/mL，其中化合物4h对NCI-H460细胞和MCF-7细胞的半数抑制浓度IC₅₀分别为6.75μg/mL和5.58μg/mL；化合物4i对MCF-7细胞的半数抑制浓度IC₅₀达到5.19μg/mL，这些结果表明4h和4i对肿瘤细胞具有较好的杀伤抑制作用。对合成的丙烯海松酸衍生物的抑菌活性进行了定量构效关系研究（QSAR，Quantitative Structure Activity Relationship）。用量子化学软件Gaussian03W对合成的丙烯海松酰胺、丙烯海松肟酯、丙烯海松希夫碱、丙烯海松酰腙、丙烯海松酰基硫脲、丙烯海松噻二唑六大类化合物进行最低能量计算和构型的几何优化，再通过Codessa2.7.15中的最佳线性回归方法分别得到了对应于大肠杆菌的抑菌活性（IZ），相关系数为R2=0.9423的包含了5个结构描述符的最佳定量构效关系计算模型和对应于金黄色葡萄球菌的抑菌活性（IZ），相关系数为R2=0.8928的包含了5个结构描述符的最佳定量构效关系计算模型。该模型显示影响这些化合物抑制大肠杆菌活性的5个结构描述符分别是：N原子的最大静电荷、最大静电荷、H原子的最小静电荷、C原子的最大静电荷、被占据的电子水平或原子数；抑制金黄色葡萄球菌活性的5个结构描述符分别是：N原子的最小静电荷、C原子的最小静电荷、H原子的最小静电荷、分子偶极的总杂化组成、Onsager-Kirkwood溶剂能。更多还原

【Abstract】 Rosin as an important natural resource, is widely available throughout China. Rosin, aswell as its derivatives, has been developed as a starting material for synthesizing variouschemicals and/or intermediates, which are renewable alternatives/substitutes ofpetrochemical-based chemicals. Acrylopimaric acid （APA） is a Diels-Alder adduct of rosin andacrylic acid and has attracted more and more attention because of its unique structure andreactivity. In this paper, amide derivatives, oxime ester derivatives, Shiff bases derivatives,dihydrazone derivatives, diacylthiourea derivatives, thiadiazole derivatives from APA weresynthesized, and their structures were characterized by IR,1H NMR, MS, and elementalanalysis. Meanwhile, their antimicrobial activities and antitumor activities in vitro were alsoinvestigated. In the final, quantitative structure activity relationship （QSAR） of antibacterialactivities of the derivatives from APA were explored. This study was expected to guide thesynthesis of the active compounds.The antibacterial activities of the derivatives of amide, oxime ester, Shiff bases,dihydrazone, diacylthiourea, thiadiazole from APA were estimated by a disc paper method.Staphylococcus aureus （gram-positive bacteria） and Escherichia coli （Gram-negative bacteria）were selected as test species. The result shows the derivatives from APA displayed extensiveanti-bacterial activity against Staphylococcus aureus and Escherichia coli. Among them, oximeester derivatives3c （12.17mm）,3d （10.00mm） and3f （10.33mm）; Shiff bases derivatives4a（15.70mm）,4b（17.00mm）and4c （16.70mm）; dihydrazone derivatives5a （10.00mm） and5c（10.00mm）; diacylthiourea derivatives6f （10.00mm）; thiadiazole derivatives7f （10.66mm）exhibited excellent anti-bacterial activity against Escherichia coli, whereas, the diameter ofinhibition zone of reference Bromogeramine was7.90mm. Further investigation on thestructure antibacterial activity relationship is needed. The antitumor activities in vitro of the derivatives of amide, oxime ester, Shiff bases,dihydrazone, diacylthiourea, thiadiazole from APA were estimated by MTT method. Thehuman non-small cell lung cancer NCI-H460cells, human hepatoma SMMC-7721cells,human breast cancer MCF-7cells under the logarithmic growth phase were selected as testcells. The half inhibitory concentration (IC₅₀) was calculated according to improved Kou’smethod. When the IC₅₀<10μg/mL, the compound has the antitumor activity in vitro. The resultshows the derivatives from APA displayed extensive antitumor activities in vitro againstNCI-H460cells, SMMC-7721cells and MCF-7cells. Among them, the oxime ester derivative3k exhibited good antitumor activities in vitro against NCI-H460cells, SMMC-7721cells andMCF-7cells and their IC₅₀were closed to10μg/mL; the Shiff bases derivatives exhibitedexcellent antitumor activities in vitro against NCI-H460cells, SMMC-7721cells and MCF-7cells and their IC₅₀were closed to or less than10μg/mL, among the Shiff bases derivatives, thecompound4h exhibited good antitumor activities in vitro against NCI-H460cells and MCF-7cells and their IC₅₀were6.75μg/mL and5.58μg/mL respectively; the compound4i alsoexhibited good antitumor activities in vitro against MCF-7cells and its IC₅₀was5.19μg/mL.The promising results obtained from these new derivatives justify their consideration aspotential candidates.The lowest energy conformers of the derivatives of amide, oxime ester, Shiff bases,dihydrazone, diacylthiourea, thiadiazole from APA were optimized at the HF/6-31G （d） levelusing the Gaussian03W package of programs. The quantitative structure activity relationship（QSAR） corresponding to against Staphylococcus aureus and Escherichia coli activities werebuilt using the best multilinear regression in Codessa2.7.15. The statistical modelings revealthat against Escherichia coli activity was affected by the following descriptors: Max net atomiccharge for a N atom, Max net atomic charge, Min net atomic charge for a H atom, Max netatomic charge for a C atom, No. of occupied electronic levels/#of atoms; and againstStaphylococcus aureus activity was affected by the following descriptors: Min net atomiccharge for a N atom, Min net atomic charge for a C atom, Min net atomic charge for a H atom, Tot hybridization comp. of the molecular dipole, Image of the Onsager-Kirkwood solvationenergy. Such results are of great benefit to synthetic efforts to discover better compoundshaving practical uses.更多还原