Synthesis and Biological Evaluation of Novel Tricyclic Oximino Derivatives as Antitumor Agents

A series of novel alkylthio/sulfinyl-8H-thieno[2,3-b]pyrrolizin-8-oximino derivatives Ⅴ1--Ⅷ15 were designed and synthesized as antitumor agents. Their structures were confirmed using IR, ^1H NMR, elemental analysis, and MS. The antitumor activities of all the target compounds were tested by the MTT method in vitro against Bel-7402, HT-1080, SGC-7901, and A549 Cell Lines. Among them, compound Ⅵ9 displayed a promising antitumor activity superior to that of Cisplatin.     

Two new triterpenoids from Gypsophila oldhamiana

Two new triterpenoids (1–2) were isolated and elucidated from the roots of Gypsophila oldhamiana, together with four known triterpenoids (3–6). Their structures were identified to be 3β-hydroxyolean-13(18)-ene-23, 28-dioic acid (1), 3β, 12α-dihydroxy-23-carboxyolean-28, 13β-olide (2), 3β, 16α-dihydroxy-23-oxoolean-13(18)-en-28-oic acid (3), gypsogenin (4), quillaic acid (5) and gypsogenic acid (6) by spectral methods. All compounds were tested for their cytotoxicities against human tumour cell lines (lung cancer H460 and gastric cancer SGC-7901) and for their antiangiogenic effects using a zebra fish model. All compounds showed interesting antiangiogenic activities and the significant cytotoxicities against H460.     

Three new phenolic glucosides from the roots of Rheum palmatum

A novel naphthalene glucoside, rheumone A (1), with an unprecedented skeleton containing a seven-membered lactone, and two new compounds, 1-O-phloroglucinyl-2-O-galloyl-6-O-cinnamoyl-β-D-glucoside (2) and chrysophanol 1-O-β-D-(6'-O-malonyl)glucoside (3), together with three known compounds (4-6) were isolated from the roots of Rheum palmatum. Their structures were elucidated mainly by spectroscopic analysis. These compounds were evaluated in vitro for their cytotoxicities towards human hepatocellular cancer cell lines Bel-7402 and Bel-7402/5Fu, and human gastric carcinoma cell line BGC-823. None of them showed cytotoxicity with IC(50) far beyond 50 μM.     

New hydrophilic/lipophilic tetra-α-(4-carboxyphenoxy) phthalocyanine zinc-mediated photodynamic therapy inhibits the proliferation of human hepatocellular carcinoma Bel-7402 cells by triggering apoptosis and arresting cell cycle

Photodynamic therapy (PDT) is a novel and promising antitumor treatment. Phthalocyanine-mediated PDT has shown antitumor activity in some tumor cells, but the effect of new hydrophilic/lipophilic tetra-α-(4-carboxyphenoxy)phthalocyanine zinc (TαPcZn)-mediated PDT (TαPcZn-PDT) on human hepatocellular carcinoma Bel-7402 cells and underlying mechanisms have not been clarified. In the present study, therefore, the ultraviolet-visible (UV-vis) absorption spectrum and cellular localization of TαPcZn, and effect of TαPcZn-PDT on the proliferation, apoptosis, cell cycle, Bcl-2 and Fas in Bel-7402 cells were investigated by spectrophotometry, inverted microscope, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, electron microscopy, annexinV-FITC/propidium iodide double staining, DNA content and immunoblot assay, respectively. We found that an intense absorption in UV-vis absorption spectrum of TαPcZn was in the red visible region at 650-680 nm, where light penetration in tissue is efficient, that green TαPcZn localized to both plasma membrane and nuclear membrane of Bel-7402 cells, signifying that there was a selective uptake of TαPcZn in Bel-7402 cells and TαPcZn-PDT would be expected to directly damage DNA, and that TαPcZn-PDT significantly resulted in the proliferation inhibition, apoptosis induction, S cell cycle arrest, and down-regulation of Bcl-2 and Fas. Taken together, we conclude that TαPcZn-PDT inhibits the proliferation of Bel-7402 cells by triggering apoptosis and arresting the cell cycle.     

聚异戊二烯基三胺的合成及生理活性评价

设计、合成了一系列聚异戊二烯基三胺化合物,目标化合物结构均经过核磁共振谱、质谱及元素分析确认;利用MTT法测试了目标化合物对人白血病细胞K562和人肝癌细胞Bel-7402的体外抗肿瘤活性.结果表明,目标化合物对两种肿瘤细胞的生长均有较强的抑制活性.     

1-氨基-7-甲氧基-β-咔啉及其1-烷氧羰基氨基衍生物的合成和 初步抗肿瘤活性研究

以1-甲氧羰基-7-甲氧基-β-咔啉为原料经肼解、重氮化反应得1-叠氮酰基-7-甲氧基-β-咔啉(6), 再经Curtius重排、碱解反应得1-氨基-7-甲氧基-β-咔啉(2). 化合物6的Curtius重排产物与各种醇反应得1-烷氧羰基氨基-7-甲氧基-β-咔啉(3). 所得到的10个化合物结构经1H NMR, 13C NMR, MS和元素分析确证. 采用MTT法对合成的化合物进行了体外抗肿瘤活性测定, 结果表明, 在10－5 mol/L浓度下目标化合物具有一定的抗肿瘤活性, 其中化合物3e, 3g和3h对HepG2和SGC-7901抑制率均高于阳性对照物骆驼蓬碱(1).     

三唑类白杨素衍生物的设计、合成及其抗增殖活性研究

合成了2个系列的白杨素衍生物,采用噻唑蓝(MTT)法测试了所有化合物针对六种肿瘤细胞的体外抗增殖活性,包括MGC-803, BEL-7402, HepG2, HeLa, A549以及SGC-7901细胞.实验结果显示, 7-[1-(3-氟苯基)-1H-1,2,3-三唑-4-甲氧基]-白杨素(1c)与7-[1-(2-氯苯基)-1H-1,2,3-三唑-4-甲氧基]-白杨素(1g)针对MGC-803细胞的活性与先导化合物白杨素及阳性对照药5-氟尿嘧啶相比显著提高.因此,化合物1c与1g具有深入研究用以开发抗癌药物的潜能.     

二肽类膦酸酯衍生物的合成与抗肿瘤活性

为了寻找抗肿瘤活性化合物,以前期研究的含一个氨基酸结构单元的膦酸酯衍生物为基础,设计合成了15个二肽类膦酸酯衍生物(Ⅲa-Ⅲo)。采用溴化噻唑蓝四氮唑(MTT)法进行体外抗肿瘤活性测试。结果表明:该类化合物对人肺癌细胞(A-549)、人胃癌细胞(SGC-7901)和人食管癌细胞(EC-109)有潜在增殖抑制作用。其中,化合物Ⅲf对A-549和EC-109的半数抑制浓度(IC 50)分别为(6.9±1.2)和(6.3±1.0)μmol/L,化合物Ⅲn对SGC-7901和EC-109的IC 50分别为(6.7±1.0)和(6.1±1.0)μmol/L,与对照药顺铂接近。     

Studies on cytotoxic and DNA-binding properties of two ruthenium(II) complexes of a substituted phenanthroline ligand

Two chair ruthenium(II) complexes, Λ- and Δ-[Ru(bpy)₂tFMPIP]^{2 +} (bpy = bipyridyl; tFMPIP = (2′-trifluoromethylphenyl)-imidazo-[4,5-f]-[1, 10]-phenanthroline, Λ-1 and Δ-1) have been synthesized and characterized by elemental analysis, ESI-MS and ¹H-NMR. The cytotoxicity of these complexes against human hepatocarcinoma cell line Bel-7402, human intestinal adenocarcinoma cell line HCT-8, and Human lung adenocarcinoma epithelial cell line A-549 have been investigated by colorimetric MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-1H-tetrazolium bromide) assay. Both Λ-1 and Δ-1 exhibit excellent inhibitory activity against the growth of Bel-7402 and HCT-8 cells. At dosage of 5 μg/cm³, the inhibition of Λ-1 and Δ-1 against human hepatocarcinoma cell line Bel-7402 is 85 and 85%, respectively. The studies on the DNA-binding properties of these complexes with Bel-7402 cell DNA by electronic spectra and steady state emission spectra, as well as circular dichlorism spectra show that there are detectable but subtle differences between Λ-1 and Δ-1, indicating the antitumor activity of these complexes is related to their DNA-binding behaviors.     

新型肟基取代豆甾类化合物的合成及其抗肿瘤活性

以豆甾醇为原料,通过臭氧化将豆甾醇的C20—C22键断裂,再经过官能团转换,合成了22-肟基取代的单肟基化合物(3和9),6,22-二肟基取代的双肟基化合物(13和14)及3,6,22-三肟基化合物(17),其中涉及4个中间体(5~8)及目标化合物9,13,14和17共8个新化合物,其结构经~1H NMR,~(13)C NMR,IR和HR-MS(ESI)表征。采用MTT法测试了化合物对人胃癌细胞(SGC-7901)、人肝癌细胞(Bel-7404)和人体乳腺癌细胞株(He La)的体外抗肿瘤活性。结果表明,具有22-肟基取代的3-羟基-5-烯结构的豆甾化合物3对受试细胞均有一定活性,IC50分别为34±2μmol·L~(-1),32±1μmol·L~(-1)和38±3μmol·L~(-1)。但是进一步在甾核上引入肟基或羟基的其他几种类型化合物的抗肿瘤活性没有提高。     

N-烷基-1,10-菲咯啉2-甲胺La(Ⅲ)配合物的合成及抗癌活性

合成和表征了甲基、乙基、丙基、丁基和苄基N-取代1,10-菲咯啉2-甲胺衍生配体及其镧(Ⅲ)配合物. 研究了配合物对HL60人白血病、PC-3MIE8人前列腺癌、BGC-823人胃癌、MDA-MB-435人乳腺癌、Bel-7402人肝癌、Hela人宫颈癌共6种瘤株的体外抗肿瘤活性及其与DNA的作用方式. 结果表明, 该系列化合物对实验的6种瘤株均具有不同程度的生长抑制作用, 其中配合物L5LaL5对MDA-MB-435人乳腺癌和Bel-7402人肝癌的抑制效果较好, 对Bel-7402人肝癌和Hela人宫颈癌的抑制效果优于顺铂. 其作用机理可能是配合物以部分插入方式同时伴随共价和静电与DNA发生作用, 影响其基因调控与表达, 进而抑制肿瘤细胞的生长, 最终导致癌细胞凋亡.     

芳香异羟肟酸二丁基锡类抗癌化合物DBDCT和DBDMT在大鼠体内组织分布的比较

系统比较研究芳香异羟肟酸二丁基锡抗癌先导化合物二-(苯甲酰异羟肟酸)二正丁基合锡(DBDBT)配体苯环上引入不同电负性取代基团得到的化合物二-(4-氯苯甲酰异羟肟酸)二正丁基合锡(DBDCT)和二-(4-甲氧基-苯甲酰异羟肟酸)二正丁基合锡(DBDMT)在大鼠体内的组织分布规律及其差异,探讨结构-组织分布-抗癌活性间的关系.静注3min后,DBDCT可迅速分布到各组织,主要分布在肾上腺,其次是十二指肠和肾,给药10min后肝脏、肠、胃壁、肺、肌肉和脂肪等组织浓度较高;而DBDMT只能分布于脑、心脏、肾、脾等少数几种组织.前期研究中DBDCT对人肝癌Bel-7402、人胃腺癌SGC-7901、卵巢癌Hela等细胞株具有比DBDMT更强的抗癌活性可能与DBDCT在肝脏、胃壁和卵巢中有较高分布、但这三个组织中几乎检测不到DBDMT有关.可见先导化合物DBDBT的配体苯环上引入的取代基团的电负性可明显影响其相应衍生物在大鼠体内的组织分布,从而可能导致对不同组织肿瘤的抗癌活性的较大差别,该研究为先导化合物DBDBT的进一步结构优化提供参考依据.     

Biosynthesis, characterization and biological evalutation of Fe(III) and Cu(II) complexes of neoaspergillic acid, a hydroxamate siderophore produced by co-cultures of two marine-derived mangrove epiphytic fungi

A hydroxamate siderophore, neoaspergillic acid (1), and a red pigment, ferrineoaspergillin (2) which is an Fe(III) complex of 1, were produced by co-cultures of two epiphytic fungi from a rotten fruit of the mangrove Avicennia marina from the South China Sea, and a new Cu(II) complex of 1, designated as cuprineoaspergillin (3), was also prepared by treatment of 1 with cupric acetate. All the compounds (1-3) were characterized by physical and chemical techniques, including 1H NMR, ESIMS, and photoelectron energy spectra. In the bioassays, compounds 1-3 showed significant inhibitory activities against selected Gram-positive and Gram-negative bacteria, and compound 1 also exhibited moderate inhibitory activities against human cancer cell lines SPC-A-1, BEL-7402, SGC-7901 and K562.     

Apoptosis of Human Gastric Carcinoma SGC-7901 Induced by Deoxycholic Acid via the Mitochondrial-Dependent Pathway

The study aimed to evaluate the effects of deoxycholic acid (DCA) on human gastric carcinoma cell lines and to explore its mechanisms. In the present study, effects of DCA on SGC-7901 cell growth, cell cycle, and apoptosis were investigated by MTT assay, inverted microscopy, fluorescence microscopy, PI single- and FITC/PI double-staining flow cytometry, and western blotting. The study have revealed that DCA significantly inhibited the growth of SGC-7901 cells in a dose- and time-dependent manner and arrested cell cycle at G0/G1 phase. SGC-7901 cells showed typical apoptotic morphological changes after treated with DCA for 48 h. The intensity of typical apoptosis pattern- “ladders” formed by DNA in fragments of multiples of 200 base pairs was also observed. Apoptosis of SGC-7901 cells induced by DCA were associated with collapse of the mitochondrial membrane potential. DCA treatment could also increase the ratio of Bax to Bcl-2 in SGC-7901 cells. Meanwhile, the expression of p53, cyclinD1, and c-Myc were changed after DCA treatment. These results suggest that DCA induces apoptosis of gastric carcinoma cells through an intrinsic mitochondrial-dependent pathway, and the increase in the Bax/Bcl-2 ratio and collapse of the mitochondrial membrane potential may play important roles in DCA-induced apoptosis of gastric carcinoma cells.     

Synthesis and Antitumor Activity of an Analog of Phthalascidin

Ecteinascidin 743 (Et-743) is an exceedingly potent antitumor agent isolated from the extracts of the marine tunicate Ecteinascidia turbinate1 that is currently undergoing phase Ⅱ/Ⅲ clinical trials in Europe and the United States2. As the result of its …     

6,7-二甲氧基-4-哌嗪喹唑啉缩氨基硫脲衍生物的合成及体外抗肿瘤活性研究

以4,5-二甲氧基-2-氨基苯甲酸和醋酸甲眯为起始原料,经环化、氯化、取代和缩合四步反应,设计、合成了六个未见文献报道的含有缩氨基硫脲的喹唑啉衍生物4a～4f,其结构用1H NMR,13C NMR,ESI-MS,IR及元素分析测试技术进行了表征.采用MTT法测试了化合物4a～4f对人胃癌SGC-7901、人口腔表皮样癌KB和人纤维肉瘤HT-1080的体外抗肿瘤活性.初步的测试结果表明,化合物4a和4f对HT1080表现出显著的抗肿瘤活性.     

Two novel alkaloids from the stem of Saprosma hainanense and their cytotoxic activities in vitro

Two novel alkaloids, saprosmine A (1) and saprosmine B (2), were isolated from the stem of Saprosma hainanense MERR., along with five known alkaloids: marcanine A (3); cleistopholine (4); 4-methoxycarbonyl-5,10-benzogquinolinequinone (5); liriodenine (6); and quinoline (7). The chemical structures were established on the basis of extensive spectroscopic (IR, 1D-NMR, 2D-NMR, MS) data analysis and by comparison with spectroscopic data reported in the literature. Compounds 1 to 6 were evaluated for in vitro cytotoxic activities against the SPC-A-1 (human lung cancer), BEL-7402 (human hepatocellular carcinoma), SGC-7901 (human gastric cancer), and K-562 (human myelogenous leukaemia) cancer cell lines. Compounds 1 and 2 exhibited weak cytotoxic activities against K-562 cells. Compounds 3 and 5 showed cytotoxic activities against all four cancer cell lines.     

8-黄酮哌嗪衍生物的合成及生理活性研究

设计合成了4个8-黄酮甲基哌嗪和4个8-黄酮甲基多聚异戊二烯哌嗪类化合物, 产物结构均经1H NMR, ESI-MS和元素分析确认. 使用MTT法测试了8个化合物对Bel-7402 (人肝癌细胞)和K562(白血病细胞)两种肿瘤细胞的体外抗肿瘤活性. 结果表明哌嗪单黄酮和双黄酮体外生理活性并不理想, 但在黄酮骨架上引入多聚异戊二烯哌嗪基后的产物对K562细胞表现出比N,N-二(8-黄酮甲基)香叶基胺(1)更好的体外抗肿瘤活性.     

新型20(S)-O-取代苯甲酸-7-苯甲酰基喜树碱酯的合成及其抗肿瘤活性

以20(S)-喜树碱为起始原料,对其进行结构修饰,在7-位导入苯甲酰基,在20-位羟基上导入取代苯甲酰基,设计并合成了11个新的20(S）-O-取代苯甲酸-7-苯甲酰基喜树碱酯化合物（4a~4k）,其结构经¹H NMR, IR,MS(ESI)和元素分析表征。采用MTT法初步考察了目标化合物4a～4j对人胃癌细胞（BGC-823）、人乳腺癌细胞（MDA-MB-231）、人肺腺癌细胞（H460）及人肝癌细胞（Bel-7404）的体外抑制活性。结果表明：化合物4a、 4g和4h具有一定的体外抑瘤活性。在药物浓度为10 μmol·L^-1时,4a对MDA-MB-231细胞和H460细胞的抑制率分别为50.42%和54.40%, 4g〗对MDA-MB-231细胞的抑制率为69.91%, 4h对H460细胞抑制率为52.34%。     

A pair of tirucallane C27-triterpenoid cyclopentenone epimers from the stem barks of Aphanamixis grandifolia

Two novel tirucallane C₂₇-triterpenoid epimers, aphagranins A (1) and B (2), featuring an unprecedented enolized cyclopentenone presented in the side-chain at C-17, were isolated from the stem barks of Aphanamixis grandifolia. Extensive spectroscopic analyses helped the establishment of the structures of the two isolates, whose absolute configurations were determined using density functional theory (DFT) calculations of optical rotation, and electronic circular dichroism (ECD). Remarkable discrepancies in the inhibitory activities against the growth of six lines of human cancer cells (MCF-7, A549, HepG2, Bel-7402, SGC-7901, and BGC-823) were found for the two epimers: with IC₅₀ less than 10 μM, aphagranin A exhibited much stronger antiproliferative activity than aphagranin B, showing no such activities with IC₅₀ over 20 μM.