13-羟乙胺苦参碱衍生物的合成及抗肿瘤药理活性研究

以槐果碱为先导化合物,通过对槐果碱的结构修饰,得到一系列具有抗肿瘤活性的新型衍生物,旨在抗肿瘤新药研发过程中提供一定参考依据。以DMF为溶剂,乙醇胺为亲核共轭体,合成了10个新型13-羟乙胺苦参碱衍生物[13-(N-磺酰基)羟乙胺苦参碱(2a～2d),13-(N-苄基)羟乙胺苦参碱(2e～2j)]。其结构经~1H-NMR,~(13)C-NMR和MS表征,并选取肝癌细胞(HepG-2)和宫颈癌细胞(Hela)对所合成的化合物采用MTT测试法进行体外抗肿瘤药理活性初步筛选。对于两种肿瘤细胞株而言,所合成的目标化合物与苦参碱和槐果碱相比,药理活性均有不同程度的提高。其中化合物2f对于两种肿瘤细胞均显示出了较好的活性。本文成功合成了10个新型的苦参碱衍生物,实验结果显示化合物2f对于两种受试肿瘤细胞均显示出了良好的抑制活性,且活性优于槐果碱和苦参碱。这对于今后抗肿瘤新药的设计和合成,有一定的借鉴意义。     

新型腙基取代嘧啶衍生物的合成及抗肿瘤活性评价（英文）

为了寻找高效的新型抗肿瘤药物,设计并合成了一系列新型腙基取代的2,4,6-取代嘧啶衍生物,并对目标化合物在MCF-7(人乳腺癌细胞), MGC-803(人胃癌细胞系),PC-3(人前列腺癌细胞),Hela(人宫颈癌细胞)和A549(人肺癌细胞)进行抗肿瘤活性评价.结果显示部分化合物对PC-3表现出中度至强效的抗肿瘤活性.其中2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-2-基亚甲基)-肼基)-6-(三氟甲基)嘧啶(12l)对PC-3具有较强的抗增殖活性, IC_(50)为1.37μmol·L~(-1),抗肿瘤活性明显优于阳性对照药5-氟尿嘧啶,为抗肿瘤药物的研究提供了新的思路.     

生物素标记的甾体化合物探针的合成及抗肿瘤活性

分别以去氢表雄酮和孕烯醇酮为原料,通过保护3-位羟基,对甾核支链上的的羰基进行肟化,胺化,将D-生物素酰氯与胺反应,合成了新型生物素探针标记的甾体衍生物,采用红外,核磁和高分辨质谱对化合物的结构进行表征。采用MTT法,对化合物进行体外抗肿瘤活性测试,结果表明化合物8、13和14对某些肿瘤细胞株有较好的抗肿瘤活性,且对正常细胞株(HEK293T)没有明显的毒害作用。     

新型1,3-二取代酞嗪酮类衍生物的合成及抗肿瘤活性研究

为了寻找高效低毒的抗肿瘤药物,设计并合成新型的1,3位取代酞嗪酮类化合物.采用噻唑蓝(MTT)法对目标化合物在MCF-7(人乳腺癌细胞)、PC-3(人前列腺癌细胞)、SW-620(人结肠癌细胞)和HGC-27(人胃癌细胞)四种人类癌细胞的抗增殖活性进行评价.结果显示大部分化合物具有较好的抗增殖活性.其中,2-(4-(4-溴苯基)-1-氧代酞嗪-2(1H)-基)-N-(2-氟苯基)乙酰胺(5g)对MCF-7细胞的抗增殖活性较好,IC50值为6.01μmol/L,为抗肿瘤药物的研究提供了思路.     

N-乙酰基吡唑啉衍生物和二苯醚基N-乙酰基双吡唑啉衍生物的合成及体外抗肿瘤活性

合成了7个N-乙酰基吡唑啉化合物2a~2g和7个新型的二苯醚基N-乙酰基双吡唑啉化合物4a~4g,通过核磁共振谱、元素分析和质谱对合成化合物进行了结构表征.并且用3-(4,5-二甲基吡啶-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑(MTS)法测试了它们对人肺腺癌细胞(A549)、人非小细胞肺癌细胞(H1299)和乳癌细胞(MCF-7)三类癌细胞株的体外抗肿瘤活性.结果显示,所合成的化合物对癌细胞有一定抑制作用,其中3,3'-(4,4'-二苯醚基)双[1-乙酰基-5-(3,4-亚甲基二氧苯基)-2-吡唑啉](4e)对A549,H1299和MCF-7三类癌细胞株具有较好的抗肿瘤活性,半数抑制浓度(IC50)分别为16.91,10.09,10.97μmol/L.     

螺杂环单羰基姜黄素类似物的合成、晶体结构与抗肿瘤活性研究

为了发现新型姜黄素类抗肿瘤先导化合物,通过1,3-偶极环加成反应合成了14个螺杂环单羰基姜黄素类似物.该反应利用无需加催化剂的"一锅煮"方法合成,具有环境友好的优点.所有化合物结构经ESI-MS、ESI-HRMS和1H NMR确认,通过X衍射确证B6的晶体结构为单斜晶系,该类化合物的合成具有良好的区域选择性和立体选择性.通过噻唑兰(MTT)法测定所有化合物对人胃癌细胞SGC-7901、神经胶质瘤细胞U251、人大细胞肺癌细胞株NCI-H460的增殖抑制活性,部分化合物表现出了较好的活性.其中B1、B6、B7和B11对三种肿瘤细胞均表现出较好的抗肿瘤活性,而对正常人肝细胞HL-7702显示了相对较低的细胞毒性.化合物B1和B7均能明显诱导凋亡相关蛋白含半胱氨酸的天冬氨酸蛋白水解酶3(caspase3)和多聚ADP-核糖聚合酶(PARP)的活化,诱导肿瘤细胞发生凋亡.所合成的螺杂环单羰基姜黄素类似物为新型的抗肿瘤化合物,该类化合物可能在靶向抗肿瘤药物研发方面具有较好的研究前景.     

含三氟甲基的2,4-取代嘧啶衍生物的合成及抗肿瘤活性评价（英文）

为了寻找高效的新型抗肿瘤药物,设计并合成了一系列新型含三氟甲基的2,4-取代嘧啶衍生物,并对目标化合物在EC-109(人食管癌细胞),MGC-803(人胃癌细胞),PC-3(人前列腺癌细胞)和HepG-2(人肝癌细胞)进行抗肿瘤活性评价,结果显示部分化合物对PC-3表现出中度至强效的抗肿瘤活性.其中, 2-(((4-((1-甲基-1H-四唑-5-基)硫基)-6-(三氟甲基)嘧啶-2-基)硫基)甲基)苯并[d]噻唑(13w)对PC-3具有较强的抗肿瘤活性, IC_(50)为1.76μmol·L~(-1),抗肿瘤活性明显优于阳性对照药5-氟尿嘧啶.     

含苯并咪唑的2,4-取代喹唑啉衍生物的合成及抗肿瘤活性评价（英文）

为了寻找高效的抗肿瘤药物,设计并合成了一系列新型的2,4-取代喹唑啉类衍生物,采用噻唑蓝(MTT)法对目标化合物在人类胃癌细胞(MGC-803)、乳腺癌细胞(MCF-7)和人正常胃黏膜上皮细胞GES-1进行抗肿瘤活性评价,结果显示部分化合物对MGC-803和MCF-7表现出中度至强效的抗肿瘤活性.喹唑啉的4位被不同芳胺取代时,2-(((1H-苯并[d]咪唑-2-基)甲基)硫基)-N-(4-甲氧基苯基)喹唑啉-4-胺(15e)对MGC-803具有较好的抗肿瘤活性,IC50值为4.60μmol·L-1;喹唑啉的4位被不同查尔酮取代时,(E)-1-(4-((2-(((1H-苯并[d]咪唑-2-基)甲基)硫基)喹唑啉-4-基)氨基)苯基)-3-(3-硝基苯基)丙-2-烯-1-酮(15k)对MGC-803具有很强的抗肿瘤活性, IC50值为0.97μmol·L-1,明显优于化合物15e.但是化合物15e对GES-1的毒性远远大于化合物15k,化合物15k的毒性与对照药品5-氟尿嘧啶和吉非替尼相近.分子对接结果显示,化合物15k与表皮生长因子受体(EGFR)的结合模式优于15e,为研究新型的EGFR抑制剂提供了新的思路.     

6-取代喹唑啉衍生物的合成及抗肿瘤活性研究进展

喹唑啉及其衍生物作为重要的药效团,具有广谱的抗肿瘤生物活性,一直是药物化学研究的热点。本文围绕近年来6-酰胺类、卤代类、醚类、与7-位成环类、杂环类等喹唑啉衍生物的合成及其抗肿瘤活性作用机制研究进行概述,以期为活性更高、毒性更小的新型抗肿瘤化合物的设计合成提供参考。     

β-咔啉-苯并咪唑偶联物的合成及抗肿瘤活性研究（英文）

为进一步发现具有更好药理活性的新型β-咔啉类抗肿瘤药物,以L-色氨酸和不同种类的醛为原料设计并合成了一系列具有不同取代基的1,9-二取代-β-咔啉-苯并咪唑偶联物.采用噻唑蓝(MTT)法评估了目标化合物对肺癌(A549)、胃癌(BGC-823)、结肠癌(CT-26)、肝癌(Bel-7402)和乳腺癌(MCF-7)等五种肿瘤细胞株的体外抗肿瘤活性,讨论了β-咔啉环1位和9位取代基对抗肿瘤活性的影响.结果显示大多数目标化合物表现出广谱的抗肿瘤活性,获得了初步的构效关系.特别是化合物5s,在β-咔啉环9位具有苄基且苯并咪唑环上具有三氟甲基取代,对MCF-7细胞株具有最好的抗肿瘤活性,其IC₅₀值为(4.9±0.3)μmol/L,抗肿瘤活性明显优于阳性对照药顺铂.化合物5c和5q对测试的3株肿瘤细胞都表现出良好的活性且IC₅₀值小于10μmol/L;细胞划痕实验结果表明这两个化合物对A549细胞横向迁移能力有一定的抑制效果     

Quinone derivatives by chemical transformations of 16-hydroxycarnosol from Salvia species

The known diterpenes 12,16-epoxycarnosol (2), isotanshinone II (6), and (+)-neocryptotanshinone (8) were obtained by partial synthesis from 16-hydroxycarnosol (1), a C-16 hydroxylated abietatriene diterpene isolated in relative abundance from the aerial part of Salvia mellifera GREENE. The physical and spectroscopic data of these semisynthetic diterpenes were identical to those given for the natural ones in the literature. These abietane diterpenes have very interesting biological activities and the semisynthetic approach described here represents an alternative to obtain them from other major diterpenes isolated from Salvia species. Additionally, seven new semisynthetic diterpene analogues, 11,14-dioxo-12,16-epoxy-8,12-abietadien-20,7beta-olide (3), 11,14-dioxo-12,16-epoxy-8,12,15(16)-abietatrien-20,7beta-olide (4), 15,16-didehydro-12,16-epoxycarnosol (5), 1-oxoisotanshinone II (7), 16-hydroxycolumbaridione (9), 12,16-diacetoxycolumbaridione (10), and 14-methoxy-12,16-epoxycarnosol (13), were obtained from 1. The structures of the new compounds were established based on their spectroscopic data.     

Cembranoid diterpenes and a briarane diterpene from corals

Two new cembrane diterpenes (+)-polydactylide (1) and (+)-7alpha,8beta-dihydroxydeepoxysarcophine (2) together with (+)-sarcophine (3) and (+)-sarcophytoxide (4) have been isolated from the soft coral Sinularia polydactyla. The new cembrane diterpene (-)-7beta-hydroxy-8alpha-methoxydeepoxysarcophine (5) has been obtained from the soft coral Sarcophyton trocheliophorum and the known briarane diterpene briaexcavatolide W (6) from the gorgonian coral Briareum sp.The structures were determined primarily by NMR spectroscopy. The assignment of NMR signals was performed by means of (1)H-(1)H COSY, ROESY, HMQC and HMBC experiments.     

Inhibition of gastric H+, K(+)-ATPase activity by compounds from medicinal plants

H+, K(+)-ATPase enzyme is a therapeutic target for the treatment of gastric disturbances. Several medicinal plants and isolated compounds inhibit the acid gastric secretion through interaction with the proton pump. In order to add new properties to some natural constituents, five compounds, a benzylated derivative of vincoside, a diterpene (abietic acid) and three alkaloids (cephaeline, vinblastine and vindoline), were tested for their activities on gastric H+, K(+)-ATPase isolated from rabbit stomach. All the compounds inhibited H+, K(+)-ATPase activity with varied potency. The IC50 value for benzylvincoside was 121 (50-293) microM, and for abietic acid 177 (148-211) microM. The alkaloids cephaeline, vinblastine and vindoline inhibited the H+, K(+)-ATPase activity with IC50 values of 194, 761 and 846 microM, respectively. The results suggest that benzylvincoside, abietic acid and cephaeline can be important sources for the development of anti-secretor agents.     

Constituents of Caesalpinia crista from Indonesia

Ten new furanocassane-type diterpenes named, caesalpinins H-P (1-9) and norcaesalpinin F (10), were isolated from the CH(2)Cl(2) extract of the seed kernels of Caesalpinia crista, together with 13 known diterpenes. Their structures were determined based on the spectroscopic analysis. Among the isolated compounds, caesalpinin N (7) represents the first example of furanocassane-type diterpene possessing an aldehyde group at C-14.     

New tri- and tetracyclic diterpenes from Euphorbia villosa

Three new tetracyclic diterpenes were isolated from the chloroform-soluble extract of Euphorbia villosa, together with one new and one known lathyrane diterpene. The structures were elucidated by means of various spectroscopic methods, including HREI-MS, HRFAB-MS, UV, and 1D and 2D NMR techniques. Spectral analyses revealed that two of the tetracyclic compounds contain the rare 5-6-6-4 fused ring system, while the third has a 5-6-7-3 fused diterpene core. Such diterpene skeletons have previously been found only in euphoractines A-E isolated from Euphorbia micractina. As a new structural feature, the diterpene framework described here has a C-2 epimer configuration. The new lathyrane diterpene is a diester of a hitherto unknown polyfunctional parent alcohol.     

Isolation and Stucture Elucidation of Diterpenes from Wedelia prostrata and Their Cytotoxicity Activities

In this paper, a new diterpene together with seven known diterpenes was isolated from Wedelia prostrata. The chemical structure of the new compound was elucidated via 1D and 2D nuclear magnetic resonance(NMR) techniques and mass spectrometry and identified to be 3α-phenylpropionoyloxy-ent-kaur-16-en-oic acid(1). The isolated diterpenes were tested for their cytotoxicity activities via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. The results show that compounds 1, 2, 3, 4 and 6 exhibit different levels of cytotoxic activities. Especially, compound 2 shows significant cytotoxicity toward HeLa and A549 cell lines(IC₅₀=6.14 and 8.76 μmol/L).     

Novel synthetic strategy toward abietane and podocarpane-type diterpenes from (−)-sclareol: synthesis of the antitumor (+)-7-deoxynimbidiol

A new route to abietane and podocarpane-type terpenoids from labdane diterpenes is reported. The key step is the transformation of β-ketoester 9 into the corresponding O-acetylsalicylate ester 18, via a manganese(III)-based oxidative free-radical cyclization carried out in Ac₂O. Utilizing this, the synthesis of the antitumor (+)-7-deoxynimbidiol (5) from (−)-sclareol (11) has been achieved. (+)-Nimbidiol (6) and the natural terpenoid 20 have also been synthesized.     

松香烷内酯型大戟二萜化合物的研究进展

松香烷内酯是大戟属植物中提取的一种典型二萜类化合物, 其基本结构为四环二萜, 有多种药理活性, 特别是有较强的抗肿瘤活性. 对国内外已经报道的松香烷内酯型大戟二萜化合物结构进行了归纳分类, 同时综述了近年来国内外文献对此类化合物的抗肿瘤药理活性、作用机制以及合成研究的进展情况, 总结和讨论了此类化合物的构效关系, 评述了这类化合物作为抗肿瘤药物的开发潜力, 提出了目前存在的问题与不足, 并对其发展前景和研究方向做出了预测和展望.     

A new ent-clerodane diterpene from the aerial parts of Baccharis gaudichaudiana

A new ent-clerodane diterpene, named bacchariol (1) was isolated from the aerial parts of Baccharis gaudichaudiana DC. (Compositae), together with known ent-clerodane diterpenes (2, 3), eight known flavonoids (4-11) and 3, 5-dicaffeoylquinic acid (12). Their structures were determined by spectroscopic analyses. Flavonoids (7, 8, 11) and 12 showed moderate scavenging activities toward 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radicals.     

新型苄基氨基甲酸酯类化合物的合成及其抗菌活性

以邻氯苄胺为原料,经6步反应制得中间体2-氯-5-［1-(氧丙炔基亚氨基)乙基］苄基氨基甲酸甲酯（7）;取代芳基肟经氯化后再分别与7经环合反应合成了一系列新型的苄基氨基甲酸酯类化合物（10a~10l）,其结构经¹H NMR表征。初步的抗菌活性测试表明：在用药量为200 mg·L^-1时,大部分化合物对水稻纹枯病显示出较好的抗菌活性,其中10f的抑菌活性最高,抑制率95%。