2-取代苯基-5-(3′-吲哚基)-噁唑衍生物的合成及其抗氧化活性

目的　合成 5 ( 3′ 吲哚基 ) 唑衍生物并研究其抗氧化活性。方法　以色氨酸为原料 ,与取代的苯甲酸在DCC催化下脱水缩合得到酰胺 ,再通过DDQ苄位氧化和分子内环合生成 5 ( 3′ 吲哚基 ) 唑。用DPPH体外抗氧化模型测定化合物的抗氧化活性。结果　合成了 11个 2 取代苯基 5 ( 3′ 吲哚基 ) 唑衍生物 ,其中化合物 2 1和 2 2的活性比维生素E强约 3～ 4倍 ;化合物 2 9的活性与维生素E相近。结论　合成的目标化合物中有 3个化合物有较好的抗氧化活性 ,有可能开发成为良好的抗氧化剂。     

1-吲哚基取代β-咔啉生物碱及其衍生物的合成和初步抗肿瘤活性

目的设计合成eudistomin U及其6位甲氧基/溴取代衍生物和5′位溴取代衍生物并测试其抗肿瘤活性。方法以吲哚-3-甲醛或5-溴-吲哚-3-甲醛和色胺或取代色胺为原料先缩合,再通过Pictet-Spengler反应环合得到四氢-β-咔啉,然后用DDQ脱氢芳构化得到目标化合物。结果合成了eudistomin U及其6位甲氧基/溴取代衍生物和5′位溴取代衍生物,利用核磁共振、质谱、高分辨质谱确认结构。结论合成了海洋生物碱eudistomin U及其一系列衍生物,初步体外抗肿瘤试验结果表明它们均具有一定的抗肿瘤活性。     

新型含羟基E,E-1-(3′-吲哚基)-5-取代苯基-1,4-戊二烯-3-酮化合物的合成及抗炎活性

目的寻找新的非甾体抗炎药物。方法利用羟醛缩合反应,合成了8个新型含羟基的E,E-1-(3′-吲哚基)-5-取代苯基-1,4-戊二烯-3-酮化合物,通过1H NMR,ESI-MS和元素分析对其结构进行表征。并测定了体外抗炎活性。结果体外抗炎活性测试结果表明,所有化合物都有一定程度的抗炎活性。结论其中化合物4d和4 e具有较强的抗炎活性,其抗炎活性与白藜芦醇接近,值得进一步研究。     

N-芳酰基取代的二氢吲哚-3-乙酸类衍生物的设计、合成与体外降糖活性研究

目的:设计、合成N-芳酰基取代的二氢吲哚-3-乙酸类衍生物,并评价其体外降糖活性。方法:以吲哚衍生物2-[5-(苄氧基)-1-(4-氯苯甲酰基)-2-甲基-1H-吲哚-3-基]乙酸(GY3)为先导化合物,以4-苯甲氧基苯肼盐酸盐及4-氧戊酸甲酯为原料,经Fischer吲哚环合、还原、酰胺化及水解等4步反应得到8种N-芳酰基(3-羟基苯甲酰基、3-氰基苯甲酰基、4-硝基苯甲酰基、4-甲磺酰基苯甲酰基、4-乙酰胺基苯甲酰基、3-乙酰氨基苯甲酰基、异烟酰基、吡啶-2-甲酰基)取代的二氢吲哚-3-乙酸类衍生物。采用人肝癌细胞HepG2测试目标化合物的体外促葡萄糖消耗活性。结果:共合成8个N-芳酰基取代的二氢吲哚-3-乙酸类目标化合物,其结构均经质谱、核磁共振氢谱及碳谱确证。在1.0μmol/L条件下,所合成化合物在HepG2细胞上的促葡萄糖消耗百分率为5.4%～9.1%,其中,2-[(2R,3S)-5-苄氧基-2-甲基-1-(4-甲磺酰基苯甲酰基)-2,3-二氢-吲哚-3-基]乙酸的降糖活性最好,其促葡萄糖消耗百分率为(9.10±1.81)%,与阳性对照药物二甲双胍接近[(10.58±1.68)%],但仍弱于先导化合物GY3[(12.15±0.78)%]。结论:二氢吲哚类化合物的N-芳酰基芳环上引入不同吸电子取代基团,如氰基、硝基、甲磺酰基等,其降糖活性不同程度下降,且弱于卤素取代基的GY3。     

1-(5-取代糠基)吲哚啉-2-酮衍生物的合成和初步抗肿瘤活性

为了寻找具有较好抗肿瘤活性的新型吲哚啉-2-酮类化合物，本研究以5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯与5位不同取代的吲哚啉-2-酮(2a～2d)为原料，首先经缩合得3-吡咯亚甲基-吲哚啉-2-酮(3a～3d)，再经N烃化反应得到1-(5-甲酰基糠基)-3-(吡咯亚甲基)-吲哚啉-2-酮(4a～4d)，然后与吲哚啉-2-酮缩合得到以5-亚甲基糠基连接的双吲哚啉-2-酮化合物(5a～5d)。所合成的12个新型吲哚啉-2-酮类化合物的结构经核磁共振谱、质谱和元素分析确认。采用四氮唑盐(MTT)还原法测试所合成化合物的体外抗肿瘤活性，结果表明所合成的化合物均有一定的抗肿瘤作用，其中6个化合物对SPC-A1肺癌肿瘤株体外抑制活性优于舒尼替尼，特别是化合物5a～5d， IC₅₀值均小于5 μmol·L^-1，值得作为抗肿瘤药物先导化合物。     

1H-1,2,3-三氮唑乙酸酯衍生物的合成与体外抗乙肝病毒活性研究

目的 设计合成1H-1,2,3-三氮唑环衍生物，并测定其体外抗乙肝病毒活性。方法 以取代吲哚为原料，经取代、环加成反应得到14个目标化合物，通过¹H-NMR、¹³C-NMR和MS方法对化合物的结构进行表征，以HepG2.2.15为细胞模型进行抗乙肝病毒体外活性实验，测试化合物在体外对乙肝病毒e抗原(HBeAg)和乙肝病毒表面抗原(HBsAg)分泌的影响。结果与结论其中4个目标化合物能较好地抑制HBeAg和HBsAg的分泌，化合物2-(4-((5-氯-1H-吲哚-1-基)甲基)-1H-1,2,3-三唑-1-基)乙酸乙酯(IC₅₀=75.41μmol·L^-1,SI=9.23)能较好抑制HBV DNA。吲哚5号位含有吸电子基团卤素原子的化合物对抑制乙肝病毒的分泌效果较好。     

新型含羟基E,E-1-(3′-吲哚基)-5-取代苯基-1，4-戊二烯-3-酮化合物的合成及抗炎活性

目的寻找新的非甾体抗炎药物。方法利用羟醛缩合反应，合成了8个新型含羟基的E,E-1-(3′-吲哚基)-5-取代苯基-1，4-戊二烯-3-酮化合物，通过¹H NMR，ESI-MS和元素分析对其结构进行表征。并测定了体外抗炎活性。结果体外抗炎活性测试结果表明，所有化合物都有一定程度的抗炎活性。结论其中化合物4d和4e具有较强的抗炎活性，其抗炎活性与白藜芦醇接近，值得进一步研究。     

3-取代吲哚酮类化合物的合成及抗肿瘤活性

目的设计合成具有抗肿瘤活性的3-取代吲哚-2-酮类化合物,并对其抗肿瘤活性进行评价.方法以吲哚酮和苯甲醛衍生物在微波辐射条件下进行缩合反应制得目标化合物,用人肝癌HepG2细胞进行抗肿瘤活性检测.结果合成了8个化合物,其中6个未见报道.其结构均经1H-NMR、IR及ESI-MS确证.结论初步抗肿瘤活性测试结果显示化合物Ⅱe、Ⅱg有较强的活性(IC50值分别为1.4μmol·L-1和1.2μmol·L-1,小于阳性对照药5-Fu).微波辐射技术用于3-取代吲哚酮的合成,能大幅度缩短反应时间,提高收率.     

一锅法合成新型吲哚-色胺酮类化合物

目的合成新型结构的吲哚-色胺酮[6-(1H-吲哚-2-基)吲哚并[2,1-b]喹唑啉-12(5H)-酮]类化合物,并初步考察其代表性化合物3a的抗肿瘤活性。方法以2-吲哚酮为起始原料,经盐酸酸化后在过量三氯氧磷的条件下与相应的取代2-氨基苯甲酸经一锅法合成新的吲哚-色胺酮类化合物。采用MTT法考察化合物3a对不同肿瘤细胞的抑制作用。结果与结论合成了3个未见报道的新化合物,目标化合物的结构经质谱、核磁共振谱确证。活性测试结果表明,化合物3a对A549肿瘤细胞株显示出一定的抑制作用。目标化合物是在色胺酮结构中引入吲哚单元后形成的新骨架结构的化合物,将为进一步研究基于吲哚-色胺酮结构的先导化合物提供一个新的方向。     

3-取代吲哚衍生物的合成(Ⅰ)

基于吲哚衍生物和氮杂环衍生物的抗真菌活性,设计合成了含有噻二唑、三氮唑、二唑等氮杂环及其相应开链硫脲结构的吲哚衍生物和吲哚希夫碱化合物共18个,除化合物2、3和16外其余目标物未见报道,其结构经     

梭曼中毒大鼠脂质过氧化损伤及抗氧化剂的作用

目的 以大鼠血清乙酰胆碱酯酶(AChE)活力变化为梭曼(soman)中毒程度指标，研究维生素A和维生素E对急性中毒大鼠的血清、大脑和肝脏组织中超氧化物歧化酶(SOD)、一氧化氮合酶(NOS)和总抗氧化力(T—AoC)的影内，探讨抗氧化剂维生素A和维生素E对梭曼中毒大鼠AChE及脂质过氧化损伤的保护作用。方法 雄性大鼠40只，按体重随机分为阴性对照组、阳性对照组、维生素A组、维生素E组。阴性对照组和阳性对照组每日灌胃5ml/kg的菜籽油；维生素A组每日灌胃2ml/kg的维生素A；维生素E组每日灌胃2．5ml/kg的维生素E，共灌胃9d。第10日除阴性对照组外其余各组大鼠均皮下注射0．9LD50梭曼，2h后断头处死并取样。测定大鼠血清、大脑、肝脏的T—AOC、SOD和NOS及血清AChE活力。结果 梭曼中毒2h后，血清乙酰胆碱酷酶(AChE)及血清、大脑、肝脏组织中SOD活力和T—AoC水平下降，NOS活力提高；维生素A和维生素E均能提高SOD、T—AOC和AChE活力，而降低NOS活力。结论 经皮下注射0．9LD50梭曼可引起AChE活力显著下降，表明大鼠已严重中毒，中毒时伴有明显的脂质过氧化损伤。中毒前大鼠用维生素A和维生素E预处理，能够保护AChE活力，降低NOS活力，减少N0自由基的生成，同时，提高SOD、T—AoC水平。提示维生素A和维生素E对梭曼中毒有较好的预防作用。     

Synthesis of novel indolyl-1,2,4-triazoles as potent and selective anticancer agents

A diverse series of 22 indolyl-1,2,4-triazole congeners (6 and 7) have been synthesized from the reaction of indole-3-carbonitrile (4) or (5) with appropriate acid hydrazides in the presence of potassium carbonate. Synthesized compounds were evaluated for their cytotoxicity against six human cancer cell lines, and some of the compounds displayed promising activity. In particular, 3-(3',4',5'-trimethoxyphenyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole (7i) and 3-(4'-piperidinyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole (7n) were the most promising and broadly active compounds against the tested cell lines. It was interesting to note that the trimethoxyphenyl analog 7i showed twofold selective cytotoxicity against PaCa2 cell line (IC(50) 0.8 μm), whereas piperidinyl analog 7n was found to be selectively cytotoxic against MCF7 cell line (IC(50) 1.6 μm). Notably, the 4-fluorophenyl derivative 7c exhibited selective cytotoxicity against PC3 cell line (IC(50) 4 μm). The structure-activity relationship study revealed that substituents including 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 4-piperidinyl, 4-fluorophenyl and N-methylindole are beneficial for the activity of indolyl-1,2,4-triazoles (6 and 7).     

Synthesis and serotonin binding site studies of some conformationally restricted indolylethylamine analogues based on 2-amino-3-(3'-indolyl)bicyclo[2.2.2]octane

The bicycloannulation reaction between cyclohexenone and indolyl enamines yields trans-3-(cyclic amino)-2-(3'-indolyl)bicyclo[2.2.2]octan-5-ones, and these adducts are conformationally restricted analogues of indolylethylamine (tryptamine) which exhibit structure-dependent affinity for the serotonin 5HT2 and 5HT1a receptors. The stereochemistry of the isomeric endo and exo adducts obtained is assigned from the 1H NMR spectra of the specifically deuterated alkenes prepared from the ketones by the Bamford-Stevens reaction. Molecular mechanics calculations indicate that the conformational flexibility of the amino and indolyl groups is restricted through van der Waals interactions with the bridges of the bicyclic unit. These compounds inhibit the binding of [3H]ketanserin to 5HT2 sites in mouse cerebrocortical membranes, and the binding of [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) to 5HT1a sites in mouse hippocampal membranes. The endo compounds are the most potent, and molecular mechanics calculations indicate that these isomers have a less bulky bicyclo bridge proximate to the amine group and more conformational freedom about the C alpha-C beta-N(+)-H dihedral angle (tau 3). In the 5HT2 assay, endo-trans-3-(N-piperidinyl)-2-(3'-indolyl)bicyclo[2.2.2]octan-5-one (10a) is the most potent, and endo-trans-3-(N-pyrrolidinyl)-2-(3'-indolyl)bicyclo[2.2.2]oct-5-ene (12a) is the most potent in the 5HT1a assay. A phenyl-substituted adduct shows the least affinity in these two assays. These data provide insight into the structural differences between the 5HT1a and 5HT2 receptor sites.     

Ovarian toxicity in rats caused by methidathion and ameliorating effect of vitamins E and C

We have investigated the effect of subchronic administration of methidathion (MD) on ovary evaluated ameliorating effects of vitamins E and C against MD toxicity. Experimental groups were as follows: control group; a group treated with 5 mg/kg body weight MD (MD group); and a group treated with 5 mg/kg body weight MD plus vitamin E and vitamin C (MD + Vit group). MD and MD + Vit groups were given MD by gavage five days a week for four weeks at a dose level of 5 mg/kg/day by using corn oil as the vehicle. Serum malondialdehyde (MDA: an indicator of lipid peroxidation) concentration, serum activity of cholinesterase (ChE), and ovary histopathology were studied. The level of MDA increased significantly in the MD group compared with the control (P < 0.005). Serum MDA decreased significantly in the MD + Vit group compared with the MD group (P < 0.05). The activities of ChE decreased significantly both in the MD and MD + Vit groups compared with the controls ( P < 0.05). However, the decrease in the MD + Vit groups was less than in the MD group; the ChE activity in the MD + Vit group was significantly higher compared with MD group (P < 0.05). Number of ovarian follicles were significantly lower in the MD group compared to the controls (P < 0.05). Number of atretic follicles were significantly higher in the MD group than in the controls (P < 0.05). Follicle counts in MD + Vit group showed that all types of ovarian follicles were significantly higher, and a significant decrease in the number of atretic follicles compared with the MD group (P < 0.05). In conclusion, subchronic MD administration caused an ovarian damage, in addition, LPO may be one of the molecular mechanisms involved in MD-induced toxicity. Treatment with vitamins E and C after the administration of MD reduced LPO and ovarian damage.     

Lack of effects of vitamin E on aluminium-induced deficit of synaptic plasticity in rat dentate gyrus in vivo.

Aluminium (Al), has the potential to be neurotoxic in humans and animals, and is present in many manufactured foods and medicines and is also added to drinking water for purification purposes. Our previous study demonstrated that chronic Al exposure induced deficits of both long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic potential (EPSP) and population spike (PS) in rat dentate gyrus (DG) of hippocampus in vivo (Wang et al., 2001). The purpose of the present study was to investigate whether the Al-induced impairment of synaptic plasticity could be reversed by dietary supplementation with vitamin E (Vit E; alpha-tocopherol). Neonatal Wistar rats were exposed to Al from parturition throughout life by drinking 0.3% aluminium chloride (AlCl3) solution or a diet supplemented with Vit E at 500 microg/g/day with 0.3% AlCl3. The input/output (I/O) function, EPSP and PS were measured in DG area of adult rats (80-100 days of age) in response to stimulation applied to the lateral perforant path. The results showed that: (1) chronic Al exposure reduced the amplitudes of both EPSP LTP (control: 130.4+/-3%, n=7; Al-exposed: 110+/-2%, n=9, P<0.001) and PS LTP (control: 241+/-19%, n=7; Al-exposed: 130+/-7%, n=9, P<0.001) significantly. Vit E had no significant effects on the Al-induced deficits of EPSP LTP (Al-exposed: 110+/-2%, n=9; Al-exposed+Vit E: 112+/-2%, n=8, P>0.05) and PS LTP (Al-exposed: 130+/-7%, n=9; Al-exposed+Vit E: 129+/-4%, n=8; P>0.05); (2) the amplitudes of EPSP LTD (control: 84+/-4%, n=7; Al-exposed: 92+/-7%, n=9, P<0.01) and PS LTD (control: 81+/-4%, n=7; Al-exposed: 98+/-5%, n=9, P<0.001) were also decreased by Al treatment. The impaired EPSP LTD (Al-exposed: 92+/-7%, n=9; Al-exposed+Vit E: 93+/-4%, n=8, P>0.05) and PS LTD (Al-exposed: 98+/-5%, n=9; Al-exposed+Vit E: 94+/-6%, n=8, P>0.05) were also not significantly affected by Vit E treatment. It was suggested that dietary supplementation with Vit E did not reverse the impairment of synaptic plasticity induced by Al in DG in vivo.     

Methylated 2-aryl-1,4-naphtoquinone derivatives with diminished antioxidative activity

Methylated 2-aryl-1,4-naphtoquinone derivatives with diminished antioxidative activity 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthoquinone (1) is a selective 5-lipoxygenase (5-LOX) inhibitor possessing high antioxidative activity (AOA). In order to study the question if this activity corresponds to the mechanism of the 5-LOX inhibition (redox type 5-LOX inhibitor) the analogues 57-66 and their 3-methoxy derivatives 47-56 of the reference compound 1 were synthezised. These compounds are mono- and dimethylated within the benzoid molecular moiety which were tested for their 5-LOX inhibiting activity using human granulocytes and for their AOA by a chemiluminometric method. The synthesis of the test compounds runs in the following manner: Diels-Alder reaction of 1,4-benzoquinone (2) with the buta-1,3-dienes 3-8, bromination of the 1,4-naphthoquinones 9-14, arylation with 2,6-di-tert-butylphenol and substitution of bromine of the aryl-bromonaphthoquinones 33-46 by methoxy and hydroxy functions. A key step is the cc separation of the regioisomeric mixtures 25/26-31/32. The most potent 5-LOX inhibitors (IC50 = 1-3 microM) possess methylfunctions in 5-/8-position and show markedly diminished AOA compared with 1. 5-LOX inhibition and AOA in this class of compounds hence are not positively correlated.     

Pyrrolization and antioxidant function of proteins following oxidative stress

The consequences of oxidative stress on microsomal proteins were analyzed by studying their pyrrolization and the antioxidative activity of the modified proteins produced. The microsomal system consisted of freshly prepared trout muscle microsomes, which were oxidized in the presence of 5 microM Cu(2+), 1 mM Fe(3+)/5 mM ascorbate, or 1 mM Cu(2+)/10 mM H(2)O(2). Pyrroles on proteins were detected by forming Ehrlich adducts with p-(dimethylamino)benzaldehyde and by determination of epsilon-N-pyrrolylnorleucine (Pnl) by capillary electrophoresis. Their antioxidative activity was studied by testing two model pyrrolized proteins (dimeric and monomeric modified bovine serum albumin: DBSA and MBSA, respectively), which were produced in the reaction of BSA and 4,5(E)-epoxy-2(E)-heptenal. These proteins were assayed at a concentration of 10-40 microg/mL, which was selected because at this concentration both DBSA and MBSA had a concentration of Pnl similar to the Pnl concentration produced in oxidized microsomes. Both DBSA and MBSA significantly (p < 0.05) protected against lipid peroxidation, assessed by the formation of thiobarbituric acid reactive substances (TBARS), and protein damage, evaluated by amino acid analysis, for the three systems assayed, and this protection was always higher than that exhibited by BSA, which was used as control. The order of effectiveness was DBSA > MBSA > BSA and was parallel to the Pnl content in the assayed proteins. These results suggest that antioxidative activity of BSA may also be related to its ability to react with lipid oxidation products and to produce modified BSA with antioxidative activity. This mechanism may also be contributing to the antioxidative activity exhibited by many proteins.