946 resultados para 1,4-benzodiazepin-2-ones
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A convenient synthesis of new 5,6,7 ,8-tetrahydro-imidazo[ 1,2-a]pyrimidin-2-ones and 3,4,6,7 ,8,9-hexahydro-pyrimido[1 ,2a]pyrimidin-2- ones from the Baylis-Hillman adducts of acrylonitrile and their derivatives is described. A common strategy employed to achieve the syntheses of title compounds involved generation of diamines from different Baylis-Hillman derivatives followed by treatment with cyanogen bromide at reflux temperature to trigger a double intramolecular cyclization.
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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
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We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives 6(a–k) and their precursors 5(a–k) as potential chemotherapeutic agents. In each case, the structures of the compounds were determined by FTIR, 1H NMR and mass spectroscopy. Among the synthesized molecules, methyl 1-(4-methoxyphenethyl)-2-(4-fluoro-3-nitrophenyl)-1H-benzimidazole-5-carboxylate (5a) induced maximum cell death in leukemic cells with an IC50 value of 3 μM. Using FACS analysis we show that the compound 5a induces S/G2 cell cycle arrest, which was further supported by the observed down regulation of CDK2, Cyclin B1 and PCNA. The observed downregulation of proapoptotic proteins, upregulation of antiapoptotic proteins, cleavage of PARP and elevated levels of DNA strand breaks indicated the activation of apoptosis by 5a. These results suggest that 5a could be a potent anti-leukemic agent.
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高分子材料一般都具有某种特定的结构,这种结构将直接决定着材料的性能。当高聚物从一种结构变为另一种结构时,其材料的性能将发生改变。近来,M.Hikosaka根据聚乙烯结晶的特点,提出了“链滑移扩散理论”,认为对聚合物热处理时,其晶体片层增厚快慢与分子链的滑移扩散能力有关。反式1,4-聚丁二烯(TPBD)在常压下能以六方相稳定存在,是少有的几种具有六方相结构的聚合物。因为其六方相分子链具有较高的构象数,而各个构象之间由于能垒相差不大,构象之间很容易发生转变;因而分子链运动时相对容易,决定了六方相分子链之间的滑移扩散能力较强。为了验证M.Hikosaka的理论,特对样品在六方相温度范围进行热处理。另外由于TPBD在不同的温度下能以两种晶型稳定存在,这两种晶型之间是怎样转变的也是我们关心的问题,而且通过电镜第一次摄得了单斜相和六方相共存的电子衍射。针对上述问题我们进行了下列研究。(1)以三氯化钒体系,稀土催化剂体系合成了两种分子量的反式1,4-聚丁二烯,用IR,NMR分析高分子量样品的反式1,4结构含量为96.2%,低分子量样品反式l,4结构含量为91.2%。对两种分子量样品进行DSC研究,结果表明低分子量样品的转变温度。熔融温度均比高分子量样品低;用Thomoson-Gibbs方程计算了该样品的片层厚度,并与样品的SAXS实验结果对照,认为这种转变温度和熔点的差异除了与1,2-结构的含量有关外,也与不同分子量具有不同的片层厚度有很大关系。(2)对不同分子量的TPBD进行WAXD实验,研究了其在不同温度下的相行为及单斜相向六方相的相转变过程。以PLM为手段跟踪观察了低分子量样品的相态转变,发现许多晶粒在相转变时从视场中消失。用电镜观察到了单斜相电子衍射,六方相电子衍射及单斜相和六方相共存的电子衍射, 并发现两相结构的形貌没有大的差别。(3)用Cerius~2软件模拟了单斜相结构和六方相结构的分子链堆砌,认为单斜相向六方相发生转变时,六方相分子链构象与单斜相分子链构象相比,有序度较低,从而使其堆砌结构变得松散。同时也模拟了单斜相和六方相在晶带轴为[001]方向的电子衍射,实验观察只能得到计算机模拟所得的单斜相和六方相内层的几个电子衍射点。(4)对低分子量样品在64 ℃热处理1小时后进行的DSC,WAXD,SAXS研究表明,样品的片层厚度显著增大,结晶度也相应提高。(5)研究了高分子量样品在85 ℃和低分子量样品在53 ℃热处理不同时间后,所得的DSC曲线。结果表明随时间增加,TPBD的转变峰温度值明显增加;而且发现在前5分钟内处理样品时,结晶度都有明显增加,处理样品5分钟以后结晶度增长缓慢。对高分子量样品四次升降温时,发现降温曲线有肩峰出现,但升温曲线没有肩峰出现,把肩峰的出现归结于有小尺寸亚稳定晶体的形成。(6)对高分子量样品的六方相等温结晶数据及对由熔体快速冷却到一定温度生成单斜相的等温结晶数据进行处理,得到平衡熔点为476K,比文献值高。并利用Thomoson-Gibbs方程,得到了单斜相和六方相的温度对尺寸倒数的相图,确定了在一定尺寸下单斜相和六方相稳定存在的温度范围。(7)用电镜观察了在70 ℃热处理不同时间后所得形貌图,并讨论了样品在六方相中热处理时,样品聚集体的聚集方式。(8)研究了两种分子量样品溶液结晶时所得的球晶形貌,发现其结晶形貌与分子量有关,而且发现摄得的电子衍射是六方相电子衍射,而不是室温下稳定存在的单斜相电子衍射,认为是由于电子辐照使样品升温而发生了晶型转变。(9)用修饰后的Avrami方程,Ozawa,方程分别处理了TPBD非等温结晶数据,由Jeziorny修饰的Avrami方程分析显示TPBD的非等温结晶明显地分为一次结晶和二次结晶两个阶段,指数值n意味着一次结晶和二次结晶的成核种类,Ozawa方程分析不能很好地适用于TPBD的六方相非等温结晶数据,主要是由于Ozawa理论的不精确假定,如二次结晶,结晶温度对片层厚度相关性及整个结晶过程中恒定的冷却函数等。并由Kissinger方程得到六方相的结晶活化能为167.9kJ/mol。
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用两相滴定法测定异丙基膦酸单(1-己基-4-乙基)辛酯(PT-2,HL)在水中的溶解度S,在水中的解离常数K在水-正庚烷中的分配常数Kd及二聚常数K2,利用SOLWR计算程序,简单快速地处理两相滴定数据,得到结果为:S=3.68×10-5mol/L,pKa=5.49,logK2=4.67,logKd=2.67(25±0.5℃)
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The gas permeability and permselectivity properties were investigated of polyimides, prepared from 3,3',4,4'- and 2,2',3,3'-thiaphthalic dianhydride (p-TDPA and m-TDPA, respectively), or 1,4-bis(3,4-dicarboxyphenoxy)- and 1,4-bis(2,3-dicarboxyphenoxy) benzene dianhydride (p-HQDPA and m-HQDPA, respectively), and 4,4-oxydianiline. The polyimides prepared from meta-dianhydrides, which have lower chain-segment packing density, possess higher permeability and lower permselectivity than those prepared from para-dianhydrides. Copyright (C) 1996 Elsevier Science Ltd.
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本文选用不同微观结构、不同分子量、支化度及不同交联度的Ni-PB,用电子显微镜研究了其室温的聚集状态及低温下的结晶行为。讨论了其结构与性能的关系。
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O presente trabalho descreve o estudo da actividad e antimicrobiana de quarto derivados da quinoxalina N,N-dióxido: quinoxalina 1,4-dióxido, 2-metilquinoxalina 1,4- dióxido, 6-cloro-2,3-dimetilquinoxalina 1,4-dióxido e 3-benzoil-2-metilquinoxalina 1,4- dióxido contra as estirpes bacterianas Geobacillus stearothermophilus ATCC 10149, Escherichia coli ATCC 25922, Escherichia coli HB101, Escherichia coli (blaTEM, blaCTX-M) e Salmonella (blaCTX-M), assim como contra a estirpe de levedura Saccharomyces cerevisiae PYCC 4072. A determinação da concentração mínima inibitória (MIC) foi realizada pelo método de diluição. Os valores de MIC’s foram estimados para cada composto e estirpe. Os resultados obtidos sugerem potenciais novas drogas para quimioterapia.
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We previously demonstrated that hybrid retrotransposons composed of the yeast Ty1 element and the reverse transcriptase (RT) of HIV-1 are active in the yeast Saccharomyces cerevisiae. The RT activity of these hybrid Ty1/HIV-1 (his3AI/AIDS RT; HART) elements can be monitored by using a simple genetic assay. HART element reverse transcription depends on both the polymerase and RNase H domains of HIV-1 RT. Here we demonstrate that the HART assay is sensitive to inhibitors of HIV-1 RT. (−)-(S)-8-Chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione monohydrochloride (8 Cl-TIBO), a well characterized non-nucleoside RT inhibitor (NNRTI) of HIV-1 RT, blocks propagation of HART elements. HART elements that express NNRTI-resistant RT variants of HIV-1 are insensitive to 8 Cl-TIBO, demonstrating the specificity of inhibition in this assay. HART elements carrying NNRTI-resistant variants of HIV-1 RT can be used to identify compounds that are active against drug-resistant viruses.
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The SAR of Asperlicin analogues is reported, leading to bioactive 1,4-benzodiazepine-2-ones, which were prepared in a 3 step reaction sequence. The Asperlicin substructure was built up using Tryptophan and readily available 2-amino-acetophenones. This template, containing a 1,4-benzodiazepin-2-one moiety with a 3-indolmethyl side chain, was transformed into mono- and di-substituted 3-indol-3 '-yl-methyl-1,4-benzodi-azepine-2-ones by selective alkylation and acylation reactions. The SAR optimization of the 1,4-benzodiazepine scaffold has included variations at the 5-, 7-, 8-position, at the N1, N-indole nitrogen and the configuration of the C3-position. The most active Asperlicin analogue, having an IC50 of 1.6 microM on the CCKA receptor subtype, was obtained from Tryptophan in only 3 steps in an overall yield of 48%.
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Classical benzodiazepines, for example diazepam, interact with alpha(x)beta(2)gamma(2) GABA(A) receptors, x = 1, 2, 3, 5. Little is known about effects of alpha subunits on the structure of the binding pocket. We studied here the interaction of the covalently reacting diazepam analog 7-Isothiocyanato-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (NCS compound) with alpha(1)H101Cbeta(2)gamma(2) and with receptors containing the homologous mutation, alpha(2)H101Cbeta(2)gamma(2), alpha(3)H126Cbeta(2)gamma(2) and alpha(5)H105Cbeta(2)gamma(2). This comparison was extended to alpha(6)R100Cbeta(2)gamma(2) receptors as this mutation conveys to these receptors high affinity towards classical benzodiazepines. The interaction was studied at the ligand binding level and at the functional level using electrophysiological techniques. Results indicate that the geometry of alpha(6)R100Cbeta(2)gamma(2) enables best interaction with NCS compound, followed by alpha(3)H126Cbeta(2)gamma(2), alpha(1)H101Cbeta(2)gamma(2) and alpha(2)H101Cbeta(2)gamma(2), while alpha(5)H105Cbeta(2)gamma(2) receptors show little interaction. Our results allow conclusions about the relative apposition of alpha(1)H101 and homologous positions in alpha(2), alpha(3), alpha(5) and alpha(6) with the position occupied by -Cl in diazepam. During this study we found evidence for the presence of a novel site for benzodiazepines that prevents modulation of GABA(A) receptors via the classical benzodiazepine site. The novel site potentially contributes to the high degree of safety to some of these drugs. Our results indicate that this site may be located at the alpha/beta subunit interface pseudo-symmetrically to the site for classical benzodiazepines located at the alpha/gamma interface.
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Two new synthetic routes for the preparation of the title compound and its 3-substituted derivatives, a novel ring system present in morellin and other related natural products, are reported from the readily available dihydroanisoles.
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Studies toward the construction of functionalised piperidone derivatives from derivatives of Baylis-Hillman adducts are described. Interestingly the 6-oxo-4-aryl-piperidine-3-carboxylates generated during the study serve as precursor for the facile synthesis of 4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates
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A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.