槲皮素-3-O-酰基酯的合成及抗肿瘤活性研究

目的 合成槲皮素-3-O-酰基酯,探索抗肿瘤活性。方法 以芦丁为原料,经苄基化保护、酸水解、酯化反应,再经钯/碳(Pd/C)催化加氢脱苄基得到12种槲皮素-3-O-酰基酯,使用红外(IR)、氢谱(¹H-NMR)、碳谱(¹³C-NMR)、液质联用(ESI-MS)测定结构,采用邻二氮菲法和1,1-二苯-2-苦基肼(DPPH)法考察了12种目标化合物的抗氧化活性,采用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)法测定抗肿瘤活性。结果 光谱确定了目标化合物的结构,抗氧化性实验显示,大部分目标化合物的清除率(SC₅₀)小于槲皮素或与槲皮素相当,提示3-OH不是槲皮素抗氧化活性的必需基团,目标化合物对人食管癌细胞EC109、人食管鳞癌细胞EC9706、人胃癌细胞MGC-803、人前列腺癌细胞PC-3四株肿瘤细胞的体外增殖抑制作用增强。结论 合成了12个目标化合物,与母体槲皮素比较,对肿瘤细胞的增殖抑制作用显著增强。     

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。     

(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。     

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。     

地果化学成分及抗肿瘤活性研究

目的:研究地果化学成分及抗肿瘤活性。方法:采用硅胶柱层析、Sephadex LH-20、小孔树脂等色谱技术进行分离纯化,根据理化性质和波谱数据鉴定化合物结构。运用MTT法测定化合物对人癌细胞株A549、PC-3、K562的抑制作用。结果:从地果中分离纯化并鉴定了10个化合物,分别为:佛手柑内酯(1)、齐墩果酸(2)、棕榈酸(3)、β-香树脂醇棕榈酸酯(4)、熊果酸(5)、二十九烷(6)、日耳曼醇乙酸酯(7)、三十烷酸(8)、亚油酸(9)、豆甾烷-3β,5α,6β-三醇(10)。体外抗肿瘤活性筛选表明:化合物5对人前列腺癌细胞株(PC-3)、人白血病细胞株(K562)、人胃癌细胞株(A549)3种癌细胞株都有较强的抑制的活性,化合物2、3对PC-3和K562有一定的抑制作用,化合物1只对PC-3有抑制作用。结论:其中,化合物4～10为首次从该植物中分离得到,地果中化学成分有一定的抗肿瘤活性。     

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。     

新型4-苯胺基喹唑啉类酪氨酸激酶抑制剂的抗肿瘤活性研究

目的对合成的新型4-苯胺基喹唑啉类酪氨酸激酶抑制剂TYIG1~TYIG9进行抗肿瘤活性研究,为寻找具有靶向抗肿瘤活性的候选化合物提供依据。方法采用均相时间分辨荧光（HTRF）法对化合物进行EGFR、VEGFR-2两个靶点的体外活性筛选;采用MTS法对化合物进行肿瘤细胞（A431、A549、H1975、MDA-MB-231）增殖抑制的体外活性评价;采用人肺癌H1975细胞的移植瘤裸鼠模型评价其在动物体内抗肿瘤活性。结果采用HTRF法从合成的一系列化合物中筛选出化合物TYIG4~TYIG9对EGFR、VEGFR-2激酶的活性较好。MTS法检测得到这6个化合物对4种肿瘤细胞（A431、A549、H1975、MDA-MB-231）均有不同程度的抑制作用,其中TYIG6的增殖抑制作用的选择性更为突出;体内试验结果表明TYIG6能够剂量相关性地抑制肿瘤生长,50、100 mg/kg TYIG6对H1975的相对肿瘤抑制率分别为42.59%、34.92%。结论 TYIG6具有良好的体内外抗肿瘤活性,具有成为新型双靶点酪氨酸激酶抑制剂的潜能,有进一步的研究价值。     

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。     

安息香化学成分及其体外抗肿瘤活性

目的:对安息香化学成分进行体外抗肿瘤细胞的药效筛选,以明确安息香抗肿瘤的物质基础。方法:运用硅胶柱色谱、中压液相制备色谱、制备液相色谱等技术对安息香的95%乙醇提取物进行了系统的分离,根据理化性质和波谱数据鉴定化合物的结构;通过体外人肝癌细胞(Hep G2),人肺癌细胞(A549),人宫颈癌细胞(He La),人乳腺癌细胞(MCF-7),人前列腺癌细胞(PC-3)筛选化合物抗肿瘤活性。结果:从安息香醇提取物中分离得到15个化合物,分别鉴定为myricadiol(1),3-keto-oleanonic acid(2),(4E)-1,5-bis (4-hydroxyphenyl)-1-methoxy-2-(methoxy-methyl)-4-pentene (3a和3b),(E)-p-coumaryl alcoholγ-Ο-methyl ether(4),芝麻素(5),5-(3″-benzoyloxypropyl)-7-methoxy-2-(3’,4’-methylenedioxy phenyl)-benzofuran(6),邻苯二甲酸二丁酯(7),香草酸甲酯(8),对羟基苯甲醛(9),对羟基苯乙酮(10),香草乙酮(11),3-oxo-olean-11,13(18)-dien-28,19β-olide(12),香草醛(13),苯甲酸(14),逞罗树脂酸(15)。其中,化合物1~11为首次从安息香中分离得到。部分化合物有一定的抗肿瘤活性,其中化合物2和12抗肿瘤活性最为显著,对5种肿瘤细胞都有显著的抑制作用,显著优于阳性药顺铂。结论:安息香中萜类化合物在抗肿瘤药物的开发、应用上具有良好发展前景。     

含有吡唑或二氢吡唑结构片段的青蒿苯基醚类化合物的设计、合成及抗肿瘤活性研究

青蒿素分离自菊科植物黄花蒿,其衍生物二氢青蒿素对多种疟疾有效,抗疟疾作用已经得到广泛认可。通过近年来的研究表明,二氢青蒿素在抗肿瘤方面也有显著效果,其通过抑制肿瘤细胞增殖、促进细胞凋亡以及对肿瘤细胞的细胞毒作用来抑制肿瘤细胞的生长。该文以二氢青蒿素为先导化合物,通过杂合原理,设计了一系列含吡唑或二氢吡唑结构片段的青蒿苯基醚衍生物,以期望提高该类化合物的抗肿瘤作用。合成了14个未见文献报道的化合物,结构均经LC-MS和1H-NMR确证。以二氢青蒿素为阳性对照,采用MTT法考察了14个目标化合物对人乳腺癌细胞MCF-7及耐药细胞MCF/Adr的生长抑制活性,并测定了目标化合物对人前列腺癌细胞PC-3及雌激素非依赖型乳腺癌细胞MDA-MB-231的生长抑制作用。活性结果表明目标化合物的生长抑制活性均优于母体,对4种肿瘤细胞的抗增殖作用较母体化合物提高了几十到几百倍不等,尤其对耐药细胞MCF/Adr表现出强效的抑瘤作用,化合物5e和6f对MCF-7/Adr细胞活性突出,GI50为20 nmol·L-1左右,值得深入研究。     

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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 synthesize the derivatives of 8-amino benzofuran[3,2-d]pyrimidine and study their anticancer activities.METHODS The target compounds were synthesized through a series of reactions, and their anticancer activities in vitro were evaluated against COLO205, MCF-7 and K562 cell lines by MTT as assay. RESULTS Nine title compounds were synthesized and confirmed by EI-MS,¹H-NMR and ¹³C-NMR.Compounds 2, 3d and 5c had good inhibition effect against COLO205, MCF-7 and K562 cells.The inhibition rates of compound 5c against COLO205, MCF-7 and K562 cells were 99.58%,78.75% and 98.68% respectively at 10^-4 mol??L^-1. CONCLUSION The anticancer activity of benzofuran[3,2-d] pyrimidine derivatives is worthy of further study.     

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??OBJECTIVE To explore the synthesis of novel phenylalanine dipeptide derivatives and their inhibitory effects on tumor cells. METHODS Starting from L-phenylalanine or L-tyrosine, a series of derivatives were synthesized by reaction with chloroacetyl chloride, followed by condensation with L-phenylalaninol or L-phenylalanine methyl ester hydrochloride and nucleophilic substitution reaction with differently substituted phenol.The cell proliferation inhibiting activities of the derivatives were evaluated by thiazolyl blue tetrazolium bromide(MTT)method.RESULTS Some of the target compounds showed certain inhibitory effect for leukemia cell lines K562 and HEL in vitro.Furthermore, the derivatives 3f and 3q had preferably inhibitory effect on K562 cell line prostate cancer PC3 cells in vitro.CONCLUSION Phenylalanine dipeptide derivatives possess good effect on the leukemia and prostate cancer cells and are worth of further research.     

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??OBJECTIVE To investigate the cytotoxic activities of chemical constituents in alcohol extract of the stem bark of Murraya exotica L. METHODS The cytotoxicity against five cancer cell lines, U937,HL-60,K562,Bel7402 and Hela, were assayed by MTT and SRB METHODS. The constituents were isolated from Murraya exotica L. by routine chromatographic METHODS and the structures of the isolates were elucidated by NMR techniques. The antitumor effect was evaluated on cancer cells in vitro. RESULTS When the cancer cells were exposed to the extract for more than 48 h, the survival rate decreased with the increase of the drug concentration. Four compounds were isolated and identified as isolariciresinol (??), dimethoxy isolariciresinol (??), 3-methoxyisolariciresinol (??), and 5??-methoxyisolariciresinol (??). CONCLUSION The active ingredients in Murraya exotica L. have antitumor activities, which may be compounds ??and ??.     

薯蓣皂苷元衍生物的合成和抗肿瘤活性研究

目的合成薯蓣皂苷元衍生物并研究其体外抗肿瘤活性。方法以薯蓣皂苷元为原料,选择性地合成一系列运用AutoDock4.2对接设计的薯蓣皂苷元衍生物。采用噻唑蓝(MTT)法考察了目标化合物对人恶性黑色素瘤细胞A375、人肺腺癌细胞A549、人肝癌细胞HepG-2以及人慢性髓原白血病细胞K562进行体外抗肿瘤活性试验。结果合成12个新化合物,其结构经1H-NMR和13C-NMR确定,药理实验结果表明,大部分化合物有一定的抗肿瘤活性。结论大部分化合物有良好的抗肿瘤活性而对正常细胞无毒或低毒性。     

Triterpenoid pyrazines and benzopyrazines with cytotoxic activity

Twelve lupane, 18alpha-oleanane, and des-E-lupane derivatives (1a-5b) were either extracted from natural sources or synthesized from betulinic acid (1a) and betulin (2). Compounds 1b, 1c, 3b, 3c, 4b, 4c, 5a, and 5b were then used as starting materials for further synthesis of a series of pyrazines and benzopyrazines (6a-18); 20 of them are new (6a-6e, 7a-7d, and 10a-18). Activity of pyrazine 6a against the T-lymphoblastic leukemia cell line CEM encouraged us to synthesize several new esters (6b-6d) to study structure-activity relationships with respect to substitution of the carboxyl group at position 28. The synthesized compounds were tested for cytotoxicity against a variety of cancer cell lines of different histogenetic origin, and the results were compared with cytotoxicity of the known starting compounds. Significant cytotoxic activity against A 549, K 562, and multidrug-resistant K 562-tax cell lines was found in pyrazines 6a, 6d, and 6e.     

Synthesis of A-seco derivatives of betulinic acid with cytotoxic activity

In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS(50) 4 and 5 micromol/L) and seco-anhydrides 22 and 23 (TCS(50) 7 and 6 micromol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2).     

Antiproliferative activity of three methoxylated flavonoids isolated from Zeyheria montana Mart. (Bignoniaceae) leaves

The present study isolated three major active flavonoids, two flavones named 4',5,7-trimethoxy-luteolin (1) and 6-hydroxy-5,7-dimethoxyflavone (2) and the flavanone 5-hydroxy-6,7-dimethoxyflavanone (3) from Zeyheria montana dichloromethane leaf extract. Isolation and purification were conducted with the application of column chromatography and structures were assigned by spectral analysis. All compounds were evaluated for cytotoxic activities against human tumor cell lines UACC-62 (melanoma), MCF-7 (breast), NCI-ADR/RES (breast expressing phenotype multiple drug resistance), 786-0 (renal), NCI-H460 (lung, non-small cells), PC-3 (prostate), OVCAR-3 (ovarian), HT-29 (colon) and K562 (leukemia) in vitro. All compounds were active in different degrees on several tumor cell lines and flavanone 3 showed cytotoxicity against almost all cell lines, particularly against human NCI-ADR/RES and K562 cell lines. In conclusion, three antiproliferative compounds were isolated for the first time from Zeyheria montana and its leaves were characterized as an important source of methoxylated flavones and flavanone as potential antitumor compounds.     

粟米草三萜类化学成分及其活性研究

目的研究粟米草Mollugo pentaphylla中的三萜类化学成分,寻找其中具有细胞毒活性化合物。方法综合运用大孔吸附树脂、硅胶柱色谱、半制备型高效液相及SephadexLH-20凝胶柱色谱等各种色谱技术进行系统化学研究,根据其理化性质和MS、NMR等波谱数据鉴定化合物结构,同时对所得的三萜皂苷进行细胞毒活性测试。结果从粟米草干燥地上部分醇提取物中共分离得到6个三萜类化合物,分别鉴定为粟米草苷E(1)、3-O-[α-L-rhamnopyranosy1(1→2)-α-L-arabinopyranosyl]-28-O-[β-D-glucopyranosyl (1→6)-β-D-glucopyranosyl] oleanolic acid(2)、竹节香附皂苷R8(3)、竹节香附素A(4)、mollugogenolsA(5)、齐墩果酸(6)。细胞毒活性显示,化合物1~5对人前列腺癌DU145细胞、人宫颈癌HeLa细胞及人早幼粒白血病HL-60细胞均显示一定的抑制作用,尤其是对人早幼粒急性白血病HL-60细胞,其IC50分别为10.21、38.43、40.28、20.59、83.16μmol/L。结论化合物1为新的齐墩果酸型三萜皂苷,2~4为首次从该植物中分离得到。细胞毒活性显示,化合物1~5对人前列腺癌DU145细胞、人宫颈癌HeLa细胞及人早幼粒白血病HL-60细胞均显示一定的抑制作用。