A new class of antimalarial drugs: derivatives of benzothiopyrans.

A series of substituted benzothiopyrans was synthesized and examined for antimalarial activity. Some were found to be active and curative at dose levels of 160--360 mg/kg against Plasmodium berghei in mice. Afew observations concerning structure-activity relationships were made. The benzothiopyrans were prepared by treatment of either the gem-dichloro- or the thionothioflavone intermediate with various primary amines. The thionothioflavone intermediates were made from thioflavones. Condensation of thiophenols with benzoyl acetates gave the thioflavones.     

不同产地槐米炮制前后主成分的含量变化对α－葡萄糖苷酶活性抑制的影响

目的：比较研究10批不同产地槐米炒制前后对槐米中芦丁,槲皮素的含量变化及其对α－糖苷酶活性抑制作用的影响。方法对10批不同产地的槐米药材分别进行炒制,采用高效液相色谱法分别测定各槐米药材提取液中芦丁和槲皮素含量;以对硝基苯酚－β－1,4－葡萄糖苷（ pNPG）为底物,阿卡波糖为阳性对照,测定各槐米药材提取液对α－葡萄糖苷酶活性抑制率,比较了芦丁和槲皮素含量变化对α－葡萄糖苷酶的抑制活性的影响。结果经过炒制后,10批槐米炒制品中的芦丁含量均有所降低,而槲皮素含量则明显升高;槐米炒制品对α－糖苷酶活性抑制作用均优于生品。结论不同产地槐米炮制后,由于槲皮素含量的普遍升高,导致了槐米炒制品对α－葡萄糖苷酶活性抑制作用升高,表明槲皮素在对α－糖苷酶抑制活性起着重要作用。在治疗糖尿病疾病时选用炒制槐米更为合理。     

Antithrombotic and antiallergic activities of daidzein,a metabolite of puerarin and daidzin produced by human intestinal microflora

To evaluate the antithrombotic activities of puerarin and daidzin from the rhizome of Pueraria lobata, in vitro and ex vivo inhibitory activities of these compounds and their metabolite, daidzein, were measured. These compounds inhibited ADP- and collagen-induced platelet aggregation. Daidzein was the most potent. However, when puerarin and daidzin were intraperitoneally administered, their antiaggregation activities were weaker than when these compounds were administered orally. When in vivo antithrombotic activities of these compounds against collagen and epinephrine were measured, these compounds showed significant protection from death due to pulmonary thrombosis in mice. To evaluate the antiallergic activity of puerarin, daidzin, and daidzein, their inhibitory effects on the release of beta-hexosaminidase from RBL 2H3 cells and on the passive cutaneous anaphylaxis (PCA) reaction in mice were examined. Daidzein exhibited potent inhibitory activity on the beta-hexosaminidase release induced by DNP-BSA and potently inhibited the PCA reaction in rats. Daidzein administered intraperitoneally showed the strongest inhibitory activity and significantly inhibited the PCA reaction at doses of 25 and 50mg/kg with inhibitory activity of 37 and 73%, respectively. The inhibitory activity of intraperitoneally administered daidzein was stronger than those of intraperitoneally and orally administered puerarin and daidzin. Therefore we believe that puerarin and daidzin in the rhizome of Pueraria lobata are prodrugs, which have antiallergic and antithrombotic activities, produced by intestinal microflora.     

Phenolic Compounds from the Leaves of Stewartia pseudocamellia Maxim. and their Whitening Activities

The half-dried leaves of Stewartia. pseudocamellia were extracted with hot water (SPE) and partitioned with n-hexane (SPEH), dichloromethane (SPED), and ethyl acetate (SPEE) successively. SPE and SPEE showed significant inhibitory effects against melanogenesis and tyrosinase activities. By bioassay-guided isolation, ten phenolic compounds were isolated by column chromatography from SPEE. The whitening effect of the isolated compounds from SPEE were tested for the inhibitory activities against melanogenesis using B16 melanoma cells, in vitro inhibition of tyrosinase, and L-3,4-dihydorxy-indole-2-carboxylic acid (L-DOPA) auto-oxidation assay. A cytotoxic activity assay was done to examine the cellular toxicity in Raw 264.7 macrophage cells. Of the compounds isolated, gallic acid and quercetin revealed significant inhibitory activities against melanogenesis compared to arbutin. In particular, quercetin exhibited similar inhibitory activities against tyrosinase and L-DOPA oxidation without cytotoxicity. These results suggested that SPE could be used as a potential source of natural skin-whitening material in cosmetics as well as in food products.     

脑靶向N_1-羧酰-5-氟尿嘧啶系列化合物体外透过血脑屏障抑制肿瘤细胞活性

目的研究已合成的N1-羧酰-5-氟尿嘧啶系列化合物体外透血脑屏障抑制人星形胶质瘤细胞的活性。方法利用台盼蓝染色显微镜法观察计数方法考查N1-羧酰-5-氟尿嘧啶系列前体药物体外对人星形胶质瘤细胞增殖活性抑制作用;并通过培养大鼠脑毛细血管内皮细胞,建立体外模拟血脑屏障模型,观察N1-维甲酰-5-氟尿嘧啶和N1-山梨酰-5-氟尿嘧啶体外透过血脑屏障模型对人星形胶质瘤细胞增殖活性抑制作用。结果该系列化合物抗人星形胶质瘤活性较5-氟尿嘧啶增强,而对大鼠脑毛细血管内皮细胞的毒性降低;N1-维甲酰-5-氟尿嘧啶和N1-山梨酰-5-氟尿嘧啶较5-氟尿嘧啶透过BBB抑制人星形胶质瘤细胞的作用更好。结论N1-羧酰-5-氟尿嘧啶系列化合物抗人星形胶质瘤活性及透过体外血脑屏障能力都较5-氟尿嘧啶好。     

Anticancer agents: tumor cell growth inhibitory activity and binary QSAR analysis

The tumor cell growth inhibitory activities (log 1/GI(50)) of 166 anticancer agents studied at the National Cancer Institute (NCI) in vitro anticancer screening program have allowed us to analyze the relative importance of physicochemical parameters in influencing the inhibitory activities. Increased molecular weight, as measured by the logarithm of molecular weight (log MW), is found to be an important contributor to the tumor cell growth inhibitory activities. The tumor cell growth inhibitory activities in different subpanels of the tumor cells are highly inter-correlated with each other. A simple binary quantitative structure-activity relationship (QSAR) model was derived from the 166 anticancer drugs, based on the tumor cell growth inhibitory activities transformed into a binary (active or inactive) data format. The model obtained can be tested with additional new data, and may be useful to identify active compounds from a large compound library to be included in high throughput screening.     

三唑硫酮双席夫碱类衍生物的合成及抗肿瘤活性研究

目的：设计和合成一系列新的1,2,4-三唑-5-硫酮双席夫碱类衍生物并测定其抗肿瘤活性。方法以3,4,5-三甲氧基苯甲醛和甘氨酸为原料经一系列反应合成目标化合物7a ～7g,经氢谱核磁共振（1 H - NMR）和红外光谱（IR）表征后在 HeLa、HCT116及 BEL -7402细胞中用噻唑蓝（MTT）法测定其抑制细胞增殖的程度初步判断化合物的体外抗癌活性。结果相对于阳性对照药顺铂,化合物7a、7b、7d、7e 和7g 对 HCT116细胞显示出显著的增殖抑制活性,7a 和7d 对 HeLa 细胞有明显的增殖抑制活性,而7d 对 BEL -7402细胞有很强的抑制作用。结论化合物7d 对3种肿瘤细胞都有显著的抑制增殖活性,但其他化合物对不同来源肿瘤细胞显示出不同的抑制能力。     

Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease

Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.     

Synthesis and antiinflammatory activity of 1,5-Diarylimidazoles

A number of 1,5-diarylimidazoles has been synthesized and evaluated for their inhibitory activities of COX-2 catalyzed PGE2 production. 1,5-Diarylimidazoles were obtained from imimes and p-toluenesulfonylmethyl cyanide (TosMIC). Imines were prepared from commercially available amines and aldehydes. Among the compounds tested, 1-(2,4-difluorophenyl)-5-(4-methylsulfonylphenyl)imidazole (2r) showed strong inhibitory activity, however, most diarylimidazoles exhibited little to low inhibitory activities against COX-2 catalyzed PGE2 production.     

Xanthine oxidase inhibitory activities and crystal structures of methoxyflavones from Kaempferia parviflora rhizome

Kaempferia parviflora (KP), a Zingiberaceae plant, is used as a folk medicine in Thailand for the treatment of various symptoms, including general pains, colic gastrointestinal disorders, and male impotence. In this study, the inhibitory activities of KP against xanthine oxidase (XOD) were investigated. The extract of KP rhizomes showed more potent inhibitory activity (38% at 500 μg/ml) than those of the other Zingiberaceae plants tested. Ten methoxyflavones were isolated from the KP extract as the major chemical components and their chemical structures were elucidated by X-ray crystallography. The structurally confirmed methoxyflavones were subjected to the XOD inhibitory test. Among them, 3,5,7,4',5'-pentamethoxyflavone and 3',4',5,7-tetramethoxyflavone showed inhibitory activities (IC(50) of 0.9 and >4 mM, respectively) and their modes of inhibition are clarified as competitive/non-competitive mixed type. To the best of our knowledge, this is the first report to present the inhibitory activities of KP, 3,5,7,4',5'-pentamethoxyflavone and 3',4',5,7-tetramethoxyflavone against XOD.     

小分子拟肽类氨肽酶N抑制剂的合成及初步活性

目的设计合成小分子拟肽类衍生物并测定其抑制氨肽酶N（APN）的活性,研究它与酶的相互作用关系。方法通过模拟APN水解底物的过渡态,以D-丙氨酸为原料,经缩合反应合成小分子拟肽类衍生物;采用体外抑酶试验测定目标化合物抑制APN的活性。结果合成了12个未见文献报道的小分子拟肽类APN抑制剂,结构经红外光谱、核磁共振氢谱及质谱确证。结论目标化合物对APN有中等程度的抑制活性,可作为先导化合物开展进一步研究。     

Constituents of the flowers of Erigeron annuus with inhibitory activity on the formation of advanced glycation end products (AGEs) and aldose reductase

Seven phenolic compounds, caffeic acid (1), 4-hydroxybenzoic acid (2), 4-methoxybenzoic acid (3), protocatechuic acid (4), eugenol O-beta-D: -glucopyranoside (5), 3,6-di-O-feruloylsucrose (6), and 3,5-di-O-caffeoylquinic acid methyl ester (7), were isolated from an EtOAc-soluble partition of the flowers of Erigeron annuus. The structures of 1-7 were determined by spectroscopic data interpretation, particularly 1D and 2D NMR studies, and by comparison of their data with those published in the literature. All the isolates were subjected to in vitro bioassays to evaluate their inhibitory activities against the formation of advanced glycation end products (AGEs) and rat lens aldose reductase (RLAR). Of the compounds, 1, 6, and 7 exhibited potent inhibitory activities against the formation of AGEs. In the RLAR assay, compound 7 showed the most potent inhibitory activity.     

Antiinflammatory activity of heat-treated Cassia alata leaf extract and its flavonoid glycoside

Antiinflammatory activities of heat-treated Cassia alata leaf extract and kaempferol 3-O-gentiobioside (K3G) isolated from C. alata as an abundant flavonoid glycoside were studied by comparing their activities with the activities of sun-dried C. alata leaf extract. We observed strong inhibitory effects on Concanavalin A-induced histamine release from rat peritoneal exudate cells both in the extracts of heat-treated and sun-dried C. alata leaves. Furthermore, the heat-treated leaf extract exhibited stronger inhibitory effects than the effects of the sun-dried leaf extract at low concentrations in the studies of Concanavalin A-induced histamine release, 5-lipoxygenase inhibition, and also inhibition of cyclooxygenases (COX-1 and COX-2), whereas K3G showed weak inhibitory effects on Concanavalin A-induced histamine release, 5-lipoxygenase, and COX-1. No anti-hyaluronidase effect was detected in any of the materials tested.     

Screening and isolation of antibiotic resistance inhibitors from herb materials-resistance inhibition of volatile components of korean aromatic herbs

The resistance inhibitory activities of 54 odorant mixtures(essential oil) from 41 Korean aromatic herbs were tested against multi-drug resistantStaphylococcus aureus SA2, which has resistances to 10 usual antibiotics including chloramphenicol. As results, combinations of 28 kinds of samples from 21 herbs and chloramphenicol have resistance inhibitory activities in dose dependent manner.     

The effect of cigarette smoking on 7-ethoxyresorufin O-deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.

Four cytochrome P-450 enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE), coumarin 7-hydroxylase (CH), 7-ethoxycoumarin O-deethylase (ECDE) and aryl hydrocarbon hydroxylase (AHH) were measured in human liver needle biopsy samples from smokers and non-smokers. Cigarette smoking was verified and quantitated by measuring plasma cotinine levels. Enzyme inhibitory monoclonal antibodies (MAb) to a 3-methylcholanthrene-induced (MAb 1-7-1) and phenobarbitone-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for each of the above activities. ERDE activity was significantly elevated in the livers of cigarette smokers, whereas AHH, CH or ECDE activities were not affected by cigarette smoking. No correlation was observed between plasma cotinine concentration and ERDE activity. MAb 1-7-1 inhibited hepatic ERDE activity to a variable extent (from 0 to 65%), but had very little or no effect on AHH, CH or ECDE activities. The inhibitory effect of MAb 1-7-1 on ERDE activity was greater than 50% in the non-smokers. MAb 2-66-3 had no inhibitory effect on any of the enzyme activities studied. In contrast to liver both ERDE and AHH on human placental microsomes from cigarette smokers were inhibited by MAb 1-7-1. The MAb 2-66-3 was without effect. Cigarette smoking induces a form of P-450 in human liver, responsible for ERDE activity, that contains an epitope recognized by MAb 1-7-1. This form of cytochrome P-450 is insensitive to MAb 2-66-3 and is not contributing to AHH, CH or ECDE activities of human liver.     

β-内酰胺酶抑制肽的活性研究

目的 通过合成和筛选具有一定抑酶作用的β-内酰胺酶抑制肽,考察其抑制活性及抑制动力学生化特征,以用于产β-内酰胺酶耐药菌所致感染的临床治疗。方法 固相合成法在计算机上三维模拟设计合成β-内酰胺酶抑制肽。选取我院08年临床分离鉴定的产酶菌8株,测定临床常用抗生素对8株细菌的MIC值,采用试管稀释法进行β-内酰胺酶抑制肽活性初步筛选。分光光度法研究抑制肽对8株产酶菌所产β-内酰胺酶的抑酶效力,Dixon作图法求取抑制常数Ki,计算相关抑制动力学参数。结果 合成了6段系列短肽分子,筛选得到3段具有抑制活性的抑制肽,抑制底物动力学研究验证3段β-内酰胺酶抑制肽具有一定抑制活性,但抑制常数均较大,其抑制方式均为竞争性抑制。结论     

青果抗人免疫缺陷病毒活性部位的筛选研究

目的:筛选青果中作用于人免疫缺陷病毒(HIV)gp41抑制HIV-1与靶细胞融合的活性部位。方法:分别用水蒸气蒸馏法、溶剂梯度萃取法获得青果挥发油、青果10%水提液的石油醚、氯仿、乙酸乙酯、正丁醇萃取部位,用酶联免疫吸附(ELISA)法检测以上各部位抑制HIV-1与靶细胞融合的活性;测定活性部位中鞣质的含量,以确定青果中非鞣质成分与活性的关系。结果:青果10%水提液的石油醚、氯仿、乙酸乙酯萃取部位均有较强的抑制HIV-1与靶细胞融合的活性,其半数抑制浓度分别为(3.97±0.38)、(26.78±0.47)、(6.80±0.10)μg.mL-1;各部位中鞣质的含量分别为8.0%、9.6%、32%。结论:青果抑制HIV与靶细胞融合的活性部位为水提液的石油醚、氯仿和乙酸乙酯萃取部位,其中石油醚萃取部位活性最强,且很可能含有非鞣质类的活性物质。     

Increase of brain endogenous monoamine oxidase inhibitory activity (tribulin) in experimental audiogenic seizures in rats: evidence for a monoamine oxidase A inhibiting component of tribulin.

Brain tribulin activity in rats with an inherited predisposition to audiogenic epilepsy was studied after seizures of different intensity were induced by an electric bell. Weak seizures (from 0 to 2 arbitrary units) did not produce any changes in endogenous inhibitory activity towards either monoamine oxidase (MAO) A or B. Moderate seizures were characterized by increases in both MAO A and MAO B inhibitory activity (up to 1.9-fold). Complete tonic epileptiform seizures with total areflexia (4 arbitrary units) induced further augmentation (up to 2.5-fold) of MAO A but not of MAO B inhibitory activity. This dissociation between the two inhibitory activities points to the existence of a separate MAO A-inhibiting component of brain tribulin which is different from isatin.     

Antibacterial compounds from the leaves of<Emphasis Type="Italic">Acanthopanax senticosus</Emphasis>

Chiisanogenin (1), hyperin (2) and chiisanoside (3) were isolated from the leaves of Acanthopanax senticosus, and were tested for their inhibitory activities against 6 strains of bacteria. Among them, chiisanogenin (1) revealed broad but moderate antibacterial activities against G (+) and G (-) bacteria, the minimum inhibitory concentration (MIC) being in the range of 50-100 microg/ml.     

人参皂甙对犬心肌Na~+、K~+-ATP酶活力的影响

人参茎叶总皂甙(GNS)和人参根总皂甙(GRS)10、20和40mg/kg,显著抑制犬心肌细胞膜Na~+,K~+-ATP酶的活力;人参茎叶二醇组皂甙(PDS)和三醇组皂甙(PTS)5、10和20mg/kg,也显著抑制Na~+,K~+-ATP酶的活力。离体实验表明:GNS、GRS、PDS和PTS在0.01、0.10和1.00g/L,对犬心肌细胞膜Na~+,K~+-ATP酶的活力均具有抑制作用。提示人参的正性肌力作用可能与其对心肌Na~+,K~+-ATP酶的抑制有关。