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Pictet-Spengler reactions for the synthesis of pharmaceutically relevant heterocycles. 合成药学上相关杂环的Pictet-Spengler反应。
Karolina Pulka

The synthesis of biologically active heterocyclic scaffolds is one of the significant challenges of modern synthetic chemistry. The Pictet-Spengler (PS) reaction, known for approximately a century, remains a particularly popular cyclization method. This review describes recent applications of the PS reaction in the total synthesis of alkaloids and biologically active analogs of tetrahydroisoquinoline and tetrahydro-β-carboline. The utility of PS cyclization in the synthesis of a range of heterocyclic scaffolds is also described.

生物活性杂环支架的合成是现代合成化学的重大挑战之一。皮克特-斯宾格勒(PS)反应,已知了大约一个世纪,仍然是一个特别流行的环化方法。本文综述了PS反应在生物碱及四氢异喹啉和四氢β-羰基碱的生物活性类似物的全合成中的最新应用。还介绍了PS环化在合成一系列杂环支架中的应用。
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引用次数: 0
Homogenous asymmetric hydrogenation: Recent trends and industrial applications. 均相不对称氢化:最新趋势和工业应用。
Andreas M Palmer, Antonio Zanotti-Gerosa

Recent advances in the field of homogeneous asymmetric hydrogenation are presented in this review. An analysis of academic literature published in the past 2 years highlights significant advances in the asymmetric hydrogenation of functional groups that previously were considered difficult to hydrogenate, as well as the emergence of novel concepts in catalysis, such as the use of non-traditional metals, phosphine-free catalysts and chiral counterions. An analysis of industry publications from 2009 and 2010 highlights more established applications of asymmetric hydrogenation reactions; these are discussed with a particular focus on practical aspects, such as catalyst selection, experimental conditions and the removal of metal residues.

本文综述了近年来均相不对称氢化反应的研究进展。对过去两年发表的学术文献的分析强调了在以前被认为难以氢化的官能团的不对称氢化方面取得的重大进展,以及催化领域新概念的出现,例如非传统金属的使用,无膦催化剂和手性反离子。对2009年和2010年行业出版物的分析强调了不对称氢化反应更成熟的应用;这些讨论特别侧重于实际方面,如催化剂的选择,实验条件和金属残留物的去除。
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引用次数: 0
Cytochrome P450 proteins: retention and distribution from the endoplasmic reticulum. 细胞色素P450蛋白:内质网的保留和分布。
Etienne P A Neve, Magnus Ingelman-Sundberg

Cytochrome P450 (CYP) is a large family of well-conserved integral membrane proteins localized primarily in the membrane of the endoplasmic reticulum (ER), where these enzymes metabolize a variety of both endogenous and exogenous compounds. It has become apparent that these microsomal CYP proteins are also present in other cellular compartments, such as the cell surface and in mitochondria, where the enzymes display catalytic activity toward CYP-specific substrates, in some cases with altered substrate specificity. CYP-drug adducts exposed at the cell surface are important mediators of idiosyncratic drug toxicities. Therefore, understanding the molecular mechanisms responsible for directing these microsomal CYPs to other, non-ER cellular compartments is important. These alternatively localized CYPs should be considered as possible drug targets and as important factors during drug discovery and development, as the detoxification capacity is lower in the compartments where such CYP proteins are located. This review discusses the mechanisms of intracellular CYP transport, and the implications of the presence of CYP proteins in extra-ER compartments for drug metabolism and toxicity.

细胞色素P450 (CYP)是一个保守的完整膜蛋白大家族,主要定位于内质网(ER)的膜,这些酶代谢各种内源性和外源性化合物。很明显,这些微粒体CYP蛋白也存在于其他细胞区室中,如细胞表面和线粒体中,这些酶对cypp特异性底物表现出催化活性,在某些情况下,底物特异性发生了改变。暴露在细胞表面的cyp药物加合物是特异性药物毒性的重要介质。因此,了解负责将这些微粒体CYPs引导到其他非内质网细胞室的分子机制是重要的。这些可选定位的CYP应被视为可能的药物靶点,也是药物发现和开发过程中的重要因素,因为这些CYP蛋白所在的隔室的解毒能力较低。本文讨论了细胞内CYP转运的机制,以及CYP蛋白在内质网外区室中的存在对药物代谢和毒性的影响。
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引用次数: 0
Recent advances in the understanding of drug-mediated infusion reactions and cytokine release syndrome. 药物介导的输液反应和细胞因子释放综合征的最新研究进展。
Mindi Walker, Dorie Makropoulos, Ram Achuthanandam, Peter J Bugelski

Infusion reactions and cytokine release syndrome (CRS) are an emerging issue in drug development and are of particular importance with the development of new therapeutic proteins. Increasing concerns regarding patient safety require a better understanding of the mechanism involved and the development of novel methods for preventing and predicting such reactions and CRS. This review discusses developments during the past few years in understanding the mechanisms that cause infusion reactions and CRS, advances in approaches to prevent CRS, the reason why preclinical animal models are unreliable predictors of CRS, and new developments in the design and analysis of in vitro screening systems for the prediction of CRS.

输注反应和细胞因子释放综合征(CRS)是药物开发中的一个新兴问题,对开发新的治疗蛋白具有特别重要的意义。对患者安全的日益关注需要更好地了解所涉及的机制,并开发预防和预测此类反应和CRS的新方法。本文综述了近年来在了解引起输液反应和CRS的机制方面的进展,预防CRS的方法的进展,临床前动物模型不可靠预测CRS的原因,以及体外筛选系统设计和分析CRS预测的新进展。
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引用次数: 0
Challenges in the prediction and modeling of oral absorption and bioavailability. 口服吸收和生物利用度预测和建模的挑战。
Paul D Metcalfe, Simon Thomas

To predict the performance of a drug following oral dosing, a thorough understanding of the dissolution, uptake and metabolism of the compound is required. In this review, approaches to in silico modeling of these processes are discussed. Although oral absorption, which is limited by dissolution and passive permeation, is to some extent predictable, bioavailability, which is influenced by first-pass metabolism in the intestines and liver, is much more difficult to predict. Much of the difficulty in predicting oral absorption and bioavailability is in the experimental quantification of solubility in the gastrointestinal tract lumen, membrane permeability, plasma protein binding, metabolism and active transport, rather than the formulating of the mathematical models.

为了预测口服给药后药物的性能,需要对化合物的溶解、吸收和代谢有透彻的了解。在这篇综述中,讨论了这些过程的计算机建模方法。虽然口服吸收受溶出和被动渗透的限制,在一定程度上是可预测的,但受肠道和肝脏首过代谢影响的生物利用度更难预测。预测口服吸收和生物利用度的大部分困难在于对胃肠道腔内溶解度、膜通透性、血浆蛋白结合、代谢和主动运输的实验量化,而不是制定数学模型。
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引用次数: 0
Using more environmentally friendly solvents and benign catalysts in performing conventional organic reactions. 使用更环保的溶剂和良性催化剂进行传统的有机反应。
Brindaban C Ranu, Amit Saha, Raju Dey

The protection of the environment from toxic materials is an area of increasing concern. This review describes selected chemical processes that use more environmentally friendly solvents and less toxic catalysts. For example, water, ionic liquids and supercritical fluids have demonstrated promising activity as alternative benign reaction media for various reactions. The advantages of neat reactions in the absence of any solvent and the use of fluorous compounds as phase-separable catalysts are also described.

保护环境免受有毒物质的侵害是一个日益受到关注的领域。本文介绍了一些使用更环保的溶剂和毒性更小的催化剂的化学工艺。例如,水、离子液体和超临界流体已被证明具有良好的活性,可以作为各种良性反应的替代介质。介绍了纯反应在无溶剂条件下的优点和使用含氟化合物作为相分离催化剂。
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引用次数: 0
The role of metabolites in predicting drug-drug interactions: focus on irreversible cytochrome P450 inhibition. 代谢物在预测药物-药物相互作用中的作用:关注不可逆的细胞色素P450抑制。
Brooke M VandenBrink, Nina Isoherranen

The irreversible inhibition of cytochrome P450 (CYP) enzymes can cause significant drug-drug interactions (DDIs). The formation of metabolites is fundamental for the inactivation of CYP enzymes. Of the 19 CYP enzyme inactivators for which the mechanism of action has been established, 10 have circulating metabolites, which are on the metabolic pathway to inactivation of the CYP enzyme. Because inactivation of CYP enzymes usually requires multiple metabolic steps, the prediction of interactions between metabolites and CYPs in vivo may require complex models and the availability of data generated in vitro from each metabolite. Data discussed in this review suggest that circulating metabolites are more important in CYP inhibition in vivo than has been acknowledged.

细胞色素P450(CYP)酶的不可逆抑制可引起显著的药物相互作用(DDI)。代谢产物的形成是CYP酶失活的基础。在已经确定作用机制的19种CYP酶灭活剂中,有10种具有循环代谢产物,这些代谢产物处于CYP酶失活的代谢途径上。由于CYP酶的失活通常需要多个代谢步骤,因此预测体内代谢物和CYP之间的相互作用可能需要复杂的模型和每个代谢物在体外产生的数据的可用性。本综述中讨论的数据表明,循环代谢产物在体内CYP抑制中比公认的更重要。
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引用次数: 0
Roles of CD44 in chemical-induced liver injury. CD44在化学性肝损伤中的作用。
Kiminori Kimura, Seishu Hayashi, Masahito Nagaki

CD44 has been identified as one of the adhesion molecules that regulate cell migration in inflamed tissue. The principal ligand of CD44 is hyaluronan, and CD44 is involved in the metabolism of this compound. Furthermore, an increasing quantity of evidence suggests that CD44 has various functions related to inflammatory disease. This review focuses on the potential roles of CD44 in the pathogenesis of chemical-induced liver injury and discusses some of the functions of this protein in pathological processes. The discovery that CD44 deficiency induces severe liver injury, (associated with an increase in hepatocyte apoptosis) rather than suppressing liver inflammation is summarized. These data suggest that targeted therapies against adhesion molecules should be monitored carefully to ensure that liver disease is not exacerbated by treatment.

CD44已被确定为炎症组织中调节细胞迁移的粘附分子之一。CD44的主要配体是透明质酸,CD44参与这种化合物的代谢。此外,越来越多的证据表明CD44具有与炎症性疾病相关的多种功能。本文综述了CD44在化学性肝损伤发病机制中的潜在作用,并讨论了该蛋白在病理过程中的一些功能。总结了CD44缺乏诱导严重肝损伤(与肝细胞凋亡增加相关)而不是抑制肝脏炎症的发现。这些数据表明,针对粘附分子的靶向治疗应仔细监测,以确保肝脏疾病不会因治疗而恶化。
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引用次数: 0
Highly reactive 4-membered ring nitrogen-containing heterocycles: Synthesis and properties. 高活性四元环含氮杂环:合成与性质。
Benito Alcaide, Pedro Almendros, Cristina Aragoncillo

4-Membered nitrogen-containing heterocycles, such as β-lactams (ie, 2-azetidinones) and azetidines, are useful substrates in organic chemistry for the design and preparation of biologically active compounds by functionalization of the different positions of the ring. In addition, these compounds are versatile building blocks for the synthesis of other types of nitrogen-containing compounds with potential biological properties. This review summarizes recent data regarding the preparation and properties of 4-membered nitrogen-containing heterocyclic rings, as well as their biological activities.

4-元含氮杂环,如β-内酰胺(即2-氮杂环丁烷酮)和氮杂环丁烷,是有机化学中通过环的不同位置的功能化设计和制备生物活性化合物的有用底物。此外,这些化合物是合成具有潜在生物特性的其他类型含氮化合物的通用构建块。本文综述了近年来4元含氮杂环的制备、性质及其生物活性的研究进展。
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引用次数: 0
Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery. 取代吲哚和螺旋吲哚的对映选择性合成及其在药物发现中的应用。
Joseph J Badillo, Nadine V Hanhan, Annaliese K Franz

This review describes recent methods for the enantioselective synthesis of oxindoles and spirooxindoles, with a particular focus on scaffolds with applications in drug discovery. The synthetic challenge of the spiro-motif and the important biological activity of spirooxindoles continue to encourage the development of creative methods to access these important structures. Unique spirocycles often result from creative synthetic methods that would not typically be identified using classical synthetic disconnections. To establish the importance of asymmetric synthesis in the context of oxindole structures, recent examples are highlighted in which stereospecific binding and differential biological activity have been demonstrated based on the configuration at the 3-position. This review is organized by type of catalyst and synthetic strategy in order to compare traditional organometallic and Lewis acid methods with more recent organocatalytic methods. A section describing multicomponent and cascade reaction strategies is also included.

本文综述了近年来对映选择性合成氧吲哚和螺吲哚的方法,重点介绍了在药物发现中的应用。螺旋基序的合成挑战和螺旋吲哚的重要生物活性继续鼓励创造性方法的发展,以获得这些重要的结构。独特的螺旋循环通常是由创造性的合成方法产生的,而这些合成方法通常不能用经典的合成断开来识别。为了确定不对称合成在氧吲哚结构中的重要性,本文强调了最近的例子,其中基于3位构型的立体特异性结合和差异生物活性已被证明。本文根据催化剂类型和合成策略对传统的有机金属和路易斯酸方法与最新的有机催化方法进行了比较。一节描述多组分和级联反应策略也包括在内。
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Current opinion in drug discovery & development
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