Utilization and metabolism of [U-14C]4' galactosyllactose (O-beta-D-galactopyranosyl-(1----4)-O-beta-D-galactopyranosyl-(1----4)- D-glucopyranose) in rats

O-beta-D-Galactopyranosyl-(1----4)-O-beta-D-galactopyranosyl- (1----4)-D-glucopyranose (designated as 4'GL) are produced from lactose with Cryptococcus laurentii OKN-4. Excretion and metabolism of 4'GL in rats were examined using a radioisotope technique. [U-14c]4'GL was synthesized from [U-14C]lactose by Cryptococcus laurentii OKN-4. The 14CO2 in expired air was counted after oral administration of [U-14C]4'GL or [U-14C]lactose in conventional rats, rats treated with antibiotics and germ-free rats. The rate of 14CO2 excretion from conventional rats given [U-14C]4'GL was slower than that from those administered [U-14C]lactose. When [U-14C]4'GL was orally administered to rats given antibiotics, there was a 2-h delay in 14CO2 excretion, as compared to conventional rats. In germ-free rats, total excretion of 14CO2 from [U-14C]-4'GL decreased to about one-third of that of conventional rats during a 24-h period. Radioactivities in the serum, liver, and carcass of the [U-14C]4'GL oral administration group were lower than those of the [U-14C]lactose oral administration group. Radioactivities in the feces and urine however, were higher in [U-14C]4'GL group than in [U-14C]lactose group.     

4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮接触生物标志物的研究进展

4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)是烟草特有亚硝胺(TSNA)中具有强烈致癌性的物质之一,NNK在人体和动物体内产生的主要代谢物是4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁醇(NNAL)和它的糖苷化合物(NNAL-N-Glucuronidec和NNAL-O-Glucuronide).NN...     

遗传毒性致癌物NNK致癌强度T25的推导

目的 采用简单易行的T25来表达NNK的致癌强度,使量化风险评估易于操作。方法 通过计算机检索、收集国内外1988-2018年间公开发表的关于NNK慢性毒性的研究文献,筛选证据清晰的文献资料,对文献的原始数据进行整理分析,找出临界剂量,通过简单的数学计算,推导出实验动物的T25,并通过系数转换为人的HT25。结果 适合于评估NNK的HT25有两篇关键文献,其HT25分别是0.02mg/(kg·d)和0.004mg/(kg·d),选择相对保守的0.004mg/(kg·d)。结论 T25作为遗传毒性致癌物的致癌强度更为简单易行。     

Evaluation of in vivo wound-healing potential of 2-[4-(2,4-dimethoxy-benzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanone derivatives

Series of 2-[4-(2,4-dimethoxy-benzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanone derivatives 9(a–d) and 10(a–d) were synthesized in good yield. The synthesized compounds were characterized by ¹H NMR, LC–MS, FTIR and elemental analysis. All the compounds were screened for in vivo wound-healing activity by incision and dead space wound models on Swiss albino rats. Significant wound healing was observed in 10b and 10d treated groups as also the epithelialization of the incision wound was faster with a high rate of wound contraction in these groups. The tensile strength of the incision wound was significantly increased in 10b and 10d compared to the Nitrofurazone, the standard skin ointment. In dead space wound model also the weight of the granulation was higher indicating increase in collagenation. The SAR correlation studies revealed that the thioamide functional linkage and electron withdrawing groups influence the wound-healing activity.     

Synthesis and leishmanicidal activities of 1-(4-X-phenyl)-N'-[(4-Y-phenyl)methylene]-1H-pyrazole-4-carbohydrazides

1H-pyrazole-4-carbohydrazides were synthesized and their leishmanicidal in vitro activities and cytotoxic effects were investigated. The drugs prototypes of these new compounds (ketoconazole, benznidazole, allopurinol and pentamidine) were also tested. It was found that among all the 1H-pyrazole-4-carbohydrazides derivatives examined, the most active compounds were those with X = Br, Y = NO2 (27) and X = NO2, Y = Cl (15) derivatives which showed to be most effective on promastigotes forms of L. amazonensis than on L. chagasi and L. braziliensis species. When tested against murine peritoneal macrophages as mammalian host cell controls of toxicity, 1-(4-Br-phenyl)-N'-[(4-NO(2)-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (27) (EC50 = 50 microM l(-1)) and 1-(4-NO2-phenyl)-N'-[(4-Cl-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (15) EC50 = 80 microM l(-1))] was reasonably toxic. However, both compounds were less toxic than pentamidine and ketoconazole. These results provide new perspectives on the development of drugs with activities against Leishmania parasite.     

烟草特有亚硝胺的致癌作用及其抑制

该文综述了烟草特有亚硝胺4-(N-亚硝基甲氨基)-1-(3-吡啶基)-1-丁酮(NNK)的致癌作用及其抑制方面的研究进展,羰基还原和α-羟基化是NNK代谢活化的主要途径,NNK致癌主要作用器官是肺,致癌可能性与个体有关.有机异硫氰酸盐是NNK致癌的强抑制剂.多食用十字花科蔬菜、多吃水果、多饮用绿茶和黑茶对吸烟者和被动吸烟者是有益的.     

Synthesis of some novel 3-(1-(1-substitutedpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-substituted phenyl-1,2,4-oxadiazoles as antifungal agents

A novel series of 3-(1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-substituted phenyl-1,2,4-oxadiazoles bearing 1,2,3-triazole and piperidine ring has been synthesized in one step from amidoxime using Carbonyl diimidazole (CDI) and K₂CO₃. All the synthesized compounds (4a-4r) are novel and evaluated for their in vitro antifungal activities. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Some of the compounds from the series like 4j was equipotent with miconazole against Cryptococcus neoformans whereas activities of compound 4m against Aspergillus niger and Aspergillus flavus were comparable to miconazole. Also compound 4r shows activity comparable to miconazole against Candida albicans, A. niger and A. flavus.     

Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyrazoles

2-Acetylbenzofuran 1 on treatment with substituted aldehydes affords the corresponding chalcones 2a-c. Treatment of the chalcones with nitromethane under Michael addition condition furnished the corresponding Michael adducts 3a-c. Cyclocondensation of the chalcones 2a and 2b with thiosemicarbazide under basic refluxing conditions gave 3-(benzofuran-2-yl)-5-(4-aryl)-4,5-dihydropyrazole-1-carbothioamides 4a,b. The pyrazolines 7a-d were synthesized by treating 4a,b with phenacyl bromides in refluxing ethanol. All the synthesized compounds were screened for their antibacterial and antifungal activities at 100 microg concentration. Some of our compounds showed excellent antimicrobial activities than control drugs.     

Design, synthesis and antifungal evaluation of 1-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-1,2,4-triazol-5(4H)-one

Based on the structure of the active site of cytochrome P450 14α-demethylase (CYP51) and the conclusions of the structure-activity relationships of azole antifungals, a series of 1-(2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-1,2,4-triazol-5(4H)-one of fluconazole analogs was synthesized. All compounds were characterized by IR, HRMS, ¹HNMR and ¹³C NMR spectroscopic analysis. Results of preliminary antifungal in vitro test using eight human pathogenic species showed that some compounds displayed comparable or even better antifungal activities than reference drug fluconazole and that compound 3i exhibited significant activity against Candida albicans being worthy of further optimization.     

Synthesis and alpha(1)-antagonist activity of derivatives of 4-chloro-5-[4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl]-3(2H)-pyrid azinone

The synthesis and evaluation of the biological activity of new 4-chloro-5-?4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl?-3(2H)-pyrid azinone derivatives are reported. The blocking activity of these compounds was determined on the pre- and postsynaptic alpha-adrenoceptors of isolated rat vas deferens.     

Synthesis,beta-adrenoceptor pharmacology and toxicology of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane hydrochloride,a short acting beta(1)-specific antagonist

The synthesis of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane hydrochloride (D140S.HCl 6), a novel short acting beta(1)-specific adrenoceptor antagonist, has been described. The antagonist potency for D140S.HCl 6 has been compared with esmolol, another short acting agent, and other well known beta-adrenoceptor antagonists in isolated rat tissue preparations. The pharmacokinetics of D140S.HCl 6 in 7 day continuous intravenous infusions and 4 weeks intravenous bolus injection studies in conscious rats and dogs have been examined in toxicology studies. The effect on the isoprenaline-induced heart rate increase and the pharmacodynamic half-life of D140S.HCl 6 has been compared with esmolol in a conscious rat model. In addition, the results of a range of toxicological studies are presented. The results indicate that D140S.HCl 6 is a highly specific beta(1)-adrenoceptor antagonist (pA(2) = 8.15+/-0.22, beta(1)/beta(2) selectivity > 4400). The in vitro studies suggest D140S.HCl is ca. ten times more potent and 60 times more beta(1)-specific than racemic esmolol. Pharmacokinetic non-linearity was seen when given as a 7 day intravenous infusion at toxicological doses above 10 mg kg(-1) h(-1) in the rat and 2.5 mg kg(-1) h(-1) in the dog. Both D140S.HCl 6 and esmolol have very short durations of action after intravenous infusion in the rat (pharmacodynamic half-life is < 15 min for D140S.HCl and 10 min for esmolol). The toxicological tests indicate that D140S.HCl 6 shows no unexpected toxicity and none of the tissue irritancy problems reported for esmolol formulations.     

Asymmetric synthesis and biological evaluation of N-cyclohexyl-4-[1-(2,4-dichlorophenyl)-1-(p-tolyl)methyl]piperazine-1-carboxamide as hCB1 receptor antagonists

We recently discovered and reported a novel series of benzhydrylpiperazine derivatives bearing an asymmetric carbon atom that are potent and selective hCB1 inverse agonists. In the present study, we used Davis-Ellmann-type sulfonamide chemistry to asymmetrically synthesize two enantiomers of the most potent racemic N-cyclohexyl-4-[1-(2,4-dichlorophenyl)-1-(p-tolyl)methyl]piperazine-1-carbo-xamide [14]. Enantiomer separation and configuration assignment were carried out. Our results indicate that the R-configuration is the more active enantiomer, displaying enhanced antagonistic activity for hCB1 receptor, better oral bioavailability, and greater efficacy in the reduction of body weight in diet-induced obese mice.     

Synthesis, characterization and antidiabetic properties of N(1)-2,4-dihydroxybenzylidene-N(4)-2-hydroxybenzylidene-S-methyl-thiosemicarbazidato-oxovanadium(IV)

A new oxovanadium(IV) chelate [VOL] (L: N(1)-2,4-dihydroxybenzylidene-N(4)-2-hydroxybenzylidene-S-methyl-thiosemicarbazidato) was synthesized and characterized by elemental analysis, conductivity and magnetic measurements, UV-vis, IR, EPR spectroscopy and mass spectrometry. The biochemical and immunohistochemical effects of the administration of the vanadium complex (VOL) into the pancreas of normal and streptozotocin-induced diabetic rats were profoundly investigated. The animals were randomly divided into four groups. Group I: control (intact) animals. Group II: control animals administered with VOL. Group III: STZ-induced diabetic animals. Group IV: STZ-induced diabetic animals administered with VOL. VOL was given to some of the experimental animals by gavage at a dose of 0.2mM/kg every day for 12 days. Blood samples were collected from animals, on 0 and 1, 6 and 12 days after STZ injection. On day 12, the pancreatic tissues were taken from the animals. The tissue sections were labelled with streptavidin biotin peroxidase technique for insulin. In the diabetic group, the blood glucose levels, aspartate and alanine transaminases, alkaline phosphatase activities were increased. But, in the diabetic+VOL groups, the blood glucose levels, aspartate and alanine transaminases, alkaline phosphatase activities were reduced. In the diabetic group, a decrease in the pancreatic glutathione levels, glutathione peroxidase and superoxide dismutase activities and an increase in the pancreatic lipid peroxidation level and catalase activities were observed. The administration of VOL to the diabetic rats reversed this diabetic effect due to its insulinomimetic effects. According to the immunohistochemical and biochemical results obtained, it was concluded that VOL can regenerate B cells of the pancreas in experimental diabetes and has an antidiabetic and protective effects on the pancreas.     

Confirmation of uterotrophic activity of 3-(4-methylbenzylidine)camphor in the immature rat

In this study we found that the ultraviolet sunscreen component 3-(4-methylbenzylidine)camphor (4MBC) is uterotrophic in immature rats when administered by either subcutaneous injection or oral gavage. These data confirm earlier reports of uterotrophic activity for this agent when administered to immature rats in the diet or by whole-body immersion; however, they are in contrast to negative unpublished immature rat uterotrophic assay results. Data also indicate that 4MBC binds to isolated rat uterine estrogen receptors and shows activity in a human estrogen receptor yeast transactivation assay; however, we considered both of these effects equivocal. In this study, we confirmed the original observation that 4MBC was active as a mitogen to MCF-7 breast cancer cells. We evaluated and discounted the possibility that the estrogenic activity of 4MBC is related to its bulky camphor group, which is of similar molecular dimensions to that of the weak estrogen kepone. Uncertainty remains regarding the mechanism of the uterotrophic activity of 4MBC.     

Synthesis and pharmacology of the putative novel muscarinic agonist (S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate]

(S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate] has been suggested to be a selective agonist at the M₁ subtype of muscarinic receptor [Lambrecht G. et al., Life Sci. 56 (1995) 815–822]. We synthesized the compound and tested its selectivity for different muscarinic receptors with binding experiments using rat cerebral cortex synaptosomal membranes and cloned human m1 to m5 receptors and by functional experiments on rabbit vas deferens preparations. There was little difference in affinity for the compound at the different cloned muscarinic receptors (IC₅₀s for displacement of ³H-N-methylscopolamine were 0.7-1.0 μM). On rabbit vas deferens preparations, (S)-4-F-MePyMcN did reduce twitch responses to electrical stimulation like the known M₁ agonist McN-A-343, but unlike McN-A-343 the compound reduced postsynaptic sensitivity to noradrenaline, ATP and KCl. Because of these additional actions, (S)-4-F-MePyMcN may not be suitable as a tool to study M₁ muscarinic receptors selectively.     

The anti-estrogenic effect of 4-chloro-1,2-diphenyl-1-(4-[2-(N,N-dimethylamino)ethoxy]phenyl)1-butene (Toremifene) on the endocrine regulation in breast cancer patients

In a combined phase I-II study the hormonal effects of Toremifene were investigated in 15-15 patients at two dose levels: 60 mg and 300 mg per os, daily. Serum estradiol, progesterone, testosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, human growth hormone were monitored by radioimmunoassay and sexual hormone binding globulin by immunoradiometric assay prior to treatment and at the 2nd, 8th and 12th weeks. The influence of Toremifene upon the hypothalamo-hypophyseal axis was also controlled by a tirotropin releasing hormone functional test using 400 micrograms tirotropin releasing hormone injection iv. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and prolactin decreased proving the antiestrogenic activity of the drug. Sexual hormone binding globulin significantly (p less than 0.002) increased by week 12 at both doses, probably due to a direct effect of Toremifene upon the liver. The increase in sexual hormone binding globulin suggests the partial estrogenic effect of the drug. The tirotropin releasing hormone induced prolactin release was also suppressed. On the basis of hormonal changes and the clinical response of patients 60 mg of Toremifene proved to be as effective as 300 mg.     

Secondhand smoke exposure within semi-open air cafes and tobacco specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentrations among nonsmoking employees

Objectives

Secondhand smoke (SHS) is a defined occupational hazard. The association though between SHS exposure in semi-open air venues and tobacco specific carcinogen uptake is an area of debate.

Material and Methods

A cross sectional survey of 49 semi-open air cafes in Athens, Greece was performed during the summer of 2008, prior to the adoption of the national smoke free legislation. All venues had at least 1 entire wall open to allow for free air exchange. Indoor concentrations of particulate matter smaller than 2.5 microns (PM_2.5) attributable to SHS were assessed during a work shift, while 1 non-smoking employee responsible for indoor and outdoor table service from each venue provided a post work shift urine sample for analysis of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).

Results

Post work shift NNAL concentrations were correlated with work shift PM_2.5 concentrations attributable to SHS (r = 0.376, p = 0.0076). Urinary NNAL concentrations among employees increased by 9.5%, per 10 μg/m³ increase in PM_2.5 concentrations attributable to SHS after controlling for the time of day and day of week.

Conclusions

These results indicate that the commonly proposed practice of maintaining open sliding walls as a means of free air exchange does not lead to the elimination of employee exposure to tobacco specific carcinogens attributable to workplace SHS.     

Synthesis and evaluation of novel 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols as antifungal agents

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and synthesized on the basis of the structure-activity relationships and antimycotic mechanism of azole antifungal agents. Their structures were confirmed by elemental analysis, IR, MS, (1)H NMR and (13)C NMR. Results of preliminary antifungal tests against six human pathogenic fungi (Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida tropicalis, inherently fluconazole-resistant Candida krusei, Candida glabrata) in vitro showed that all title compounds exhibited activity against fungi tested to some extent except against C. tropicalis. Compound 5b showed higher activity against C. albicans, C. parapsilosis and C. krusei than fluconazole, and its MIC values were determined to be 0.5microg/mL, 1microg/mL and 4microg/mL, respectively. Compound 5k showed higher activities against Torulopsis glabrata than fluconazole (with the MIC value of 2microg/mL). Compounds 5a, 5c, 5f, 5g, 5i exhibited higher activities against C. parapsilosis than fluconazole (with the MIC values of 2microg/mL, 2microg/mL, 2microg/mL, 1microg/mL and 2microg/mL, respectively).     

右旋反式氯丙炔菊酯的合成及其药效研究

目的研制一种新型卫生杀虫剂--右旋反式氯丙炔菊酯.方法采用右旋反式DV菊酸与S-炔丙醇酮为原料,经化学拆分、酰氯化及酯化等反应合成右旋反式氯丙炔菊酯,并采用GB/T13917.1-1992和GB/T17322.2-1998标准方法测定了对致倦库蚊和德国小蠊的药效.结果右旋反式氯丙炔菊酯对致倦库蚊及德国小蠊的KT50值分别为8.5 min和3.46min.结论右旋反式氯丙炔菊酯对蚊虫和蟑螂等害虫具有良好的击倒作用和杀灭能力,可以作为一种新型卫生杀虫剂加以推广和应用.