槲皮素-3-O-酰胺类衍生物的合成及其抗癌活性研究

目的设计并合成槲皮素酰胺类衍生物,并对该系列化合物进行体外抗肿瘤活性研究。方法以廉价的芦丁为原料,经苄基选择性保护、Williamson成醚反应,再经Pd/C催化加氢脱苄基得到目标产物,采用DPPH法考察目标化合物的抗氧化活性,MTT法考察目标化合物对人食管鳞癌细胞EC109、人食管鳞癌细胞EC9706、人胃癌细胞SGC7901及小鼠黑色素瘤细胞B16-F10的增殖抑制作用。结果合成的15个槲皮素酰胺类衍生物结构均经¹H-NMR、¹³C-NMR、ESI-MS确证。抗氧化活性结果显示大部分目标化合物的半数清除率(SC₅₀)小于槲皮素或与槲皮素相当,这提示3-OH不是槲皮素抗氧化活性的必需基团。抗肿瘤实验结果显示,通过化学方法对槲皮素进行结构修饰后,其体外抗肿瘤活性显著增强。其中,化合物7-6对EC109细胞的抑制作用(IC₅₀=10.25μmol/L)明显优于母药槲皮素(IC₅₀=31.884μmol/L)和5-FU(IC₅₀=41.738μmol/L),是...     

4-氨基-2-三氟甲基喹唑啉衍生物的合成及其体外抗肿瘤活性研究

目的 基于喹唑啉为母核设计发现新型抗肿瘤活性化合物。方法 以邻氨基苯甲酰胺和三氟乙酸酐为起始原料采用缩合、环化、氯代和偶联反应等合成了一系列4-氨基-2-三氟甲基喹唑啉衍生物(5a~5u)。采用四甲基偶氮唑盐(MTT)法评价所得目标化合物对人肺癌细胞A549、人宫颈癌细胞Hela、人白血病细胞K562、人前列腺癌细胞PC-3、人前列腺癌细胞LNCaP这5种肿瘤细胞的体外增殖抑制活性。结果 化合物5c在5 μmol·L^-1时对PC-3肿瘤细胞的抑制率为49.3%,化合物6a对LNCaP和K562、以及6b对PC-3的抑制率超过了50.0%。结论 本实验设计合成的4-氨基-2-三氟甲基喹唑啉类化合物多数具有一定的抗肿瘤活性,特别是4-氨基的N-甲基化产物6a、6b的体外抗肿瘤活性较原型化合物(5n与5u)显著增强,为该类化合物的进一步研究提供参考。     

长叶纽子果根化学成分的研究

目的 研究长叶纽子果根(Ardisia virens Kurz var. annamensis Pitard.)的化学成分。方法 长叶纽子果根体积分数70%乙醇提取物采用硅胶柱、Sephadex LH-20、ODS、制备液相进行分离纯化,根据波谱信息鉴定所得化合物的结构。结果 在长叶纽子果根中分离得到10个化合物,分别鉴定为11-O-咖啡酸岩白菜素(1)、11-O-(3',4'-二甲基没食子酰基)岩白菜素(2)、11-O-乙酰岩白菜素(3)、岩白菜素-11-O-α-D-半乳吡喃糖苷(4)、百两金皂苷B(5)、朱砂根皂苷D(6)、朱砂根皂苷G(7)、(+)-丁香树脂酚(8)、丁香酸(9)、十八碳癸二烯酸-2,3-二羟丙基酯(10)。结论 化合物1~10为首次从该植物中分离得到。     

狼毒大戟化学成分及其生物活性研究

目的 研究狼毒大戟(Euphorbia fischeriana Steud)根部的抗肿瘤化学成分。方法 运用硅胶柱、ODS、Sephadex LH-20柱色谱以及制备HPLC等多种方法对狼毒大戟根部的体积分数95%乙醇提取物进行分离纯化,并利用HR-ESI-MS、NMR等波谱技术对分离得到的化合物进行结构鉴定。运用CCK-8检测法测定分离得到的化合物对人肝癌细胞Hep-G2、人乳腺癌细胞MCF-7和人肺癌细胞A549的细胞毒活性。结果 从狼毒大戟中共分离得到12个化合物,分别鉴定为7-oxocallitrisic acid(1)、ent-12-hydroxy-12[R]-abieta-8(14),13(15)-dien-16,12-olide(2)、13β-hydroxy-7-oxoabiet-8(14)-en-19,6β-olide(3)、decandrol A(4)、daphneaine B(5)、二氢红花菜豆酸(6)、phenethyl-6-O-α-L-arabinofuranosyl-β-D-glucoside(7)、2-(4-hydroxyphenyl)ethyl-O-α-L-arabinofuranosyl-(1→6)-O-β-D-glucopyranoside(8)、γ-pyrone-2-O-β-D-(6-galloyl)-glucopyranoside(9)、6-hydroxy-2-methoxy-4-O-α-L-arabinofurano-syl(1→6)-β-D-glucopyranoside(10)、(2,3-trans,4E)-2,3-methano-4-decen-1-ol)(11)和3, 4′-O-dimethylellagic acid(12)。结论 化合物1,4,5,7～9和11为首次从大戟属植物中分离得到,化合物1,2,4～9,11和12为首次从狼毒大戟中分离得到。化合物2对人肝癌细胞Hep-G2表现出较好的细胞毒活性,其半数抑制浓度(half maximal inhibitory concentration,IC₅₀)值为32.81 μmol·L^-1,提示该类二萜化合物可能与狼毒大戟的抗肿瘤活性相关。     

3-芳苄叉基噻唑酮-氟喹啉-4-酮氧氟沙星衍生物的合成及抗肿瘤活性

目的 进一步发现氟喹诺酮的有效结构修饰策略以提高其抗肿瘤活性。方法 基于药效团拼合药物设计原理,用噻唑酮作为氧氟沙星C-3羧基的等排体、芳苄叉基为其修饰基,构建了新的3-芳苄叉噻唑酮-氟喹啉-4-酮的氧氟沙星衍生物(6a~6l),其结构经用元素分析和光谱数据确证。MTT方法评价了体外对SMMC-7721、Capan-1和HL60这3种癌细胞株的抗增值活性。结果 12个新结构的氟喹诺酮-3-噻唑不饱和酮目标化合物被合成,其活性显著强于母体氧氟沙星1,其中卤苯基化合物强于其他取代基的活性,尤其是氯苯基化合物(6k)对Capan-1细胞的活性与对照抗肿瘤药多柔比星相当。结论 芳苄叉基噻唑酮替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。     

槲皮素-3-O-乙基苯胺类衍生物的合成及抗肿瘤活性研究

目的 合成槲皮素-3-O-乙基苯胺类衍生物并测试其抗肿瘤活性。方法 以槲皮素为先导物，选择性对C环3位羟基进行修饰。以廉价的芦丁为原料，经苄基选择性保护、Williamson成醚反应，再经Pd/C催化加氢脱苄基得到13个槲皮素-3-O-乙基苯胺类衍生物，均未见文献报道，目标产物结构经¹H-NMR、¹³C-NMR、ESI-MS确证。采用MTT法考察了13个槲皮素-3-O-乙基苯胺类衍生物对人食管鳞癌(EC109),人胃癌(HGC27),人乳腺癌(MCF-7),小鼠黑色素瘤(B16-F10)的增殖抑制作用。结果 通过化学方法对槲皮素进行结构修饰后，其体外抗肿瘤活性增强。其中，化合物5c[IC₅₀值(5.229±0.371)μmol·L^-1]、5e[IC₅₀值(2.628±0.087)μmol·L^-1]对小鼠黑色素瘤(B16-F10)抑制作用比5-氟尿嘧啶(5-FU)[IC₅₀值(14.376±0.272)μmol·L^-1     

替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物的简便合成

目的 研究替尼类药物的关键中间体N-芳基喹唑啉-4-胺化合物的新合成方法,优化反应条件,确定反应底物适用性,推测反应可能机理。方法 以取代邻氨基苯甲腈(1a～1e)和芳胺(2a～2e)为原料,甲酸为反应底物和溶剂,Cu(OTf)₂为催化剂,发生多组分串联反应一锅合成N-芳基喹唑啉-4-胺化合物(3a～3g),考察催化剂及用量、溶剂、反应物用量、反应温度和反应时间对反应的影响。结果 在Cu(OTf)₂的催化下,取代邻氨基苯甲腈、芳胺和甲酸能顺利发生串联的加成/缩合/环化反应,在取代邻氨基苯甲腈5 mmol,芳胺6 mmol,Cu(OTf)₂ 0.5 mmol,甲酸20 mL,110 ℃反应12 h的条件下,以80%～95%的收率得到7个N-芳基喹唑啉-4-胺化合物,目标产物结构经¹H-NMR和¹³C-NMR确证。结论 该方法为合成替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物提供了一种高效简便的绿色工艺,反应条件温和,产物收率高,操作安全简便,对环境友好。     

蛹虫草活性成分的提取分离及体外抗氧化作用研究

目的 以抑制蛋白酪氨酸磷酸酶1B(PTP1B)活性为导向,筛选蛹虫草子实体有效部位,分离纯化单体化合物,并检测其体外抗氧化作用。方法 通过硅胶色谱柱,半制备高效液相等色谱技术对蛹虫草子实体进行分离纯化,检测各组分对PTP1B的抑制活性;应用核磁碳谱、氢谱数据分析鉴定单体化合物结构;利用MTT法检测单体化合物对PC12细胞的增殖作用,及其对过氧化氢(H₂O₂)损伤的PC12细胞存活率的影响,试剂盒检测单体化合物对细胞乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量的影响。结果 发现5个对PTP1B具有较强抑制作用的活性成分,将其中活性最高的成分进一步分离纯化,获得单体化合物,经鉴定为β-D-吡喃葡萄糖基-9-甲基-4,8鞘氨醇(5),其对PTP1B具有较强的抑制活性,半抑制浓度(IC₅₀)为(3.42±0.59) μmol·L^-1。该单体化合物对H₂O₂诱导的PC12细胞氧化损伤具有明显的保护作用。结论 首次以抑制PTP1B活性为导向,在蛹虫草中分离得到脑苷脂类单体化合物,其具有抑制PTP1B作用和体外抗氧化活性,为蛹虫草用于糖尿病的预防和治疗奠定理论基础。     

(E)-N′-芳基亚甲基-4-(4-苯基嘧啶-2-基氨基)苯甲酰肼衍生物作为CDK9抑制剂的设计合成及抗HIV-1活性研究

目的 设计合成(E)-N′-芳基亚甲基-4-(4-苯基嘧啶-2-基氨基)苯甲酰肼衍生物,并对其抗HIV-1的活性进行研究。方法 4-氨基苯甲酸乙酯为起始原料,通过5步反应合成了目标化合物,采用荧光素酶(luciferase)报告基因检测了合成化合物对于HIV-1转录抑制活性。结果 目标化合物对于HIV-1的转录具有一定的抑制活性。其中化合物7p活性最优,在2 μmol·L^-1浓度下HIV-1转录抑制率为(73±0.05)%,在20 μmol·L^-1浓度下HIV-1转录活性为(90±0.01)%。进一步研究表明,化合物7p以浓度依赖性在NH1和NH2细胞中抑制HIV-1的转录活性以及下调RNA聚合酶Ⅱ CTD二号位丝氨酸磷酸化。最后,分子对接表明化合物7p与CDK9有很强的结合作用。结论 该系列化合物具有较好的抗HIV-1的活性,具有进一步研究的意义。     

茶藤生物碱成分的分离鉴定及抗肿瘤活性研究

目的 对茶藤Melodinus magnificus的生物碱成分进行分离、鉴定和抗肿瘤活性研究。方法 采用薄层色谱、柱色谱等色谱方法对总生物碱浸膏进行分离和纯化。通过ESI-MS、¹H-NMR、¹³C-NMR等波谱技术和文献对比等方法鉴定生物碱化合物的结构,并采用MTT法对分离得到的生物碱化合物进行抗肿瘤细胞(人肝癌HepG2细胞、乳腺癌MCF7细胞和人肺癌A549细胞)活性筛选,随后利用网络药理学和分子对接技术对具有抗肿瘤活性生物碱化合物的潜在靶点和作用通路进行预测。结果 从茶藤枝叶总生物碱中共获得10个化合物,分别鉴定为strictamine(1)、deacetylakuammiline(2)、19-(Z)-akuammidine(3)、14,15-didehydrovincamine(4)、14,15-didehydro-16-epi-vincamine(5)、19-(S)-methoxytubotaiwine(6)、19-(R)-methoxytubotaiwine(7)、rhazimine(8)、rhazicine N^4<...     

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??OBJECTIVE To synthesize 5-substituted indole-3-deoxypodophyllotoxin derivatives and study their antitumor activity. METHODS The target compounds were synthesized through a series of reactions and their anti-tumor activity in vitro were evaluated against Hela, K562 and K562/A02 cell lines by MTT as assay. RESULTS Ten target compounds were synthesized and confirmed by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS. All the target compounds had different degrees of cytotoxic activity in vitro. Most of the compounds had significant anti-MDR activity in vitro. CONCLUSION 5-Substituted indole-3-deoxypodophyllotoxin derivatives have good antitumor activity and worth of further study.     

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??OBJECTIVE To study the bioactivity and chemical constituents of different polar parts from blueberry leaves. METHODS Blueberry leaves were extracted by ethanol and then the extract was sequentially partitioned into five fractions. Silicagel and Sephadex LH-20 chromatographic methods were applied to isolate and purify compounds. Their structures were elucidated by physiochemical properties and spectral analysis.The DPPH?? radical scavenging activity, ??-glycosidase and pancreatic lipase inhibition activity of different polar parts and partial compounds were determined. RESULTS The n-butyl alcohol fraction(BF) showed the highest DPPH?? radical scavenging activity and ??-glycosidase inhibition activity. The ethyl acetate fraction(EAF) showed the strongest pancreatic lipase inhibition activity. A total of five compounds were isolated from the EAF, and their structures were identified as ??-sitosterol(1), quercetin-3-O-??-L-arabinofuranoside(2), quercetin(3), quercetin-3-O-??-D-glucopyranoside(4) and 1-O-caffeoylquinic acid(5). A total of two compounds were isolated from the BF, and their structures were identified as quercetin-3-O-??-L-arabinoside(6) and quercetin-3-O-??-D-glucuronide(7). The results showed that compounds 3 and 5 had very good DPPH?? radical scavenging and pancreatic lipase inhibitory activity, and compounds 1 and 3 had good ??-glucosidase inhibitory activity. CONCLUSION The different polar parts and compounds of blueberry leaves show strong DPPH?? radical scavenging activity, ??-glycosidase and pancreatic lipase inhibition activity. Compounds 1, 2, 5 and 6 are isolated from blueberry leaves for the first time.     

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??OBJECTIVE To design and synthesize 4-phenoxy-6,7-disubstituted quinolines possessing thiazolinone scaffolds and investigate their in vitro antitumor activities. METHODS Taking the c-Met kinase inhibitor cabozantinib as lead compound and based on the obtained SARs, combination principles and local modification, target compounds were prepared by nucleophilic substitution, nitration, reduction and condensation, etc. The c-Met inhibition and in vitro antitumor activities were evaluated by HTRF and MTT methods, respectively. The cytotoxicity against cancer cells was evaluated by real-time dynamic living cell imaging. RESULTS Seventeen novel compounds were obtained, and their structures were confirmed by ¹H-NMR, ¹³C-NMR and HRMS. In vitro bioassay indicated that all the compounds showed inhibitory activities against A549, HepG2 and MDA-MB-231 cell lines as well as c-Met kinase. Compound m2 exhibited potent cytotoxicity with IC₅₀ values of 2.45, 4.01, and 1.05 ??mol??L^-1, respectively. CONCLUSION The series of compounds show preferable antitumor activities, which are worthy of further study.     

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??OBJECTIVE To design and synthesize series of quercetin derivatives by introducing allyl or prenyl groups and investigate their antitumor activities in vitro.METHODS Compounds 2, 3, 4, 5, 6, 7 and 8 were synthesized with quercetin as starting material through the etherification reaction.The antitumor activities were evaluated by MTT assay against human lung cells (A549), human breast cancer cells (MDA-MB-231), and human hepatoma cells (HepG2).RESULTS Two allyl-substituted and five prenyl-substituted quercetin derivatives were synthesized. Compounds 4, 5, 6, 7, and 8 were new compounds, and their structures were characterized by ¹H-NMR and ¹³C-NMR. Compounds 6 and 7 exhibited observable anti-proliferative activity. Compound 6 inhibited the growth of A549, MDA-MB-231, and HepG2 cells with IC₅₀ values of 15.23, 16.56, and 12.32 ??mol??L^-1, respectively.Compound 7 restrained the growth of A549 and MDA-MB-231 cells with IC₅₀ values of 8.92 and 2.90 ??mol??L^-1, respectively. CONCLUSION Compounds 6 and 7 synthesized by introducing prenyl groups into quercetin have significant anti-tumor activities, which are worth of further research.     

新型精氨酸加压素V2受体拮抗剂的设计与生物活性研究

目的 根据药物构效关系,设计合成出一系列结构新颖的V2受体拮抗剂,以期筛选出高效低毒的此类化合物,为进行下一步的临床前研究创造条件,为新药的创制奠定基础。方法 根据“me-too”的设计思路合成一定数量结构新颖的V2受体拮抗剂。通过核磁共振氢谱(¹H-NMR)、高分辨质谱(HRMS)等手段进行结构确证,并且测定了熔点、纯度等相关理化常数。通过表达人类V2受体的细胞模型和大鼠利尿模型进行生物活性评价。结果 设计合成出12个未见文献报道的目标化合物(A1~A12),以托伐普坦为阳性对照药,其中A6,A7,A11等化合物表现出较强的生物活性,并且具有作用持续时间更长的特点。结论 化合物结构设计合理,对进一步开展V2受体拮抗剂的结构改造及其药理毒理活性研究具有一定的参考价值。     

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??OBJECTIVE To study the chemical constituents of Callicarpa nudiflora. METHODS The chemical constituents were isolated and purified by column chromatography on silica gel, ODS, Sephadex LH-20 and MPLC. Their structures were elucidated by spectroscopic evidence and compared with those in literature. RESULTS Nine compounds were isolated and identified as 6-O-caffeoyl ajugol(1), leucosceptoslde A(2), 6-O-caffeoly-??-glucose(3), nudifloside(4), luteolin-7-O-glucoside(5), quercetin 3??-O-??-D-glucoside(6), cistaneside C(7), acteoside(8), and syringalide A 3??-??-L-rhamnopyranoside (9). CONCLUSION Compounds 1, 2, 6, 7, and 9 are isolated from this plant for the first time.