Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products

The anti-oxidant naphterpin is a natural product containing a polyketide-based aromatic core with an attached 10-carbon geranyl group derived from isoprenoid (terpene) metabolism. Hybrid natural products such as naphterpin that contain 5-carbon (dimethylallyl), 10-carbon (geranyl) or 15-carbon (farnesyl) isoprenoid chains possess biological activities distinct from their non-prenylated aromatic precursors. These hybrid natural products represent new anti-microbial, anti-oxidant, anti-inflammatory, anti-viral and anti-cancer compounds. A small number of aromatic prenyltransferases (PTases) responsible for prenyl group attachment have only recently been isolated and characterized. Here we report the gene identification, biochemical characterization and high-resolution X-ray crystal structures of an architecturally novel aromatic PTase, Orf2 from Streptomyces sp. strain CL190, with substrates and substrate analogues bound. In vivo, Orf2 attaches a geranyl group to a 1,3,6,8-tetrahydroxynaphthalene-derived polyketide during naphterpin biosynthesis. In vitro, Orf2 catalyses carbon-carbon-based and carbon-oxygen-based prenylation of a diverse collection of hydroxyl-containing aromatic acceptors of synthetic, microbial and plant origin. These crystal structures, coupled with in vitro assays, provide a basis for understanding and potentially manipulating the regio-specific prenylation of aromatic small molecules using this structurally unique family of aromatic PTases.     

芳香族碳氢化合物等离子体化学反应的研究

本文研究了七种芳香族碳氢化合物的气相IR激光化学,主要是等离子体化学.实验说明.在功率密度I≤13.5GW·CM~(-2)下,它们不能通过红外多光子吸收发生可检测的反应,仅当它们与环境气体混合击穿—成等离子体时,才有明显的反应发生.反应的结果,它们均以乙炔为主要产物,并伴有少量其它小分子碳氢化合物生成.实验还证实了该条件下它们的反应属等离子体下的热反应,并非等离子体辐射引起的光反应,且初始过程中包括单分子最弱键断裂的基元反应.     

药物中间体β-卤代苯乙胺的简便合成

发展了一条高效、简单的药物中间体β-卤代苯乙胺的合成方法.二苄胺和溴乙酸乙酯作为起始原料,经历取代、加成、催化氢化、氯代和酰化5步反应,以中等产率制备得到目标产物2-乙酰氨基-3-氯-3-(4-甲氧基苯基)丙酸乙酯,对合成过程中的中间产物及目标产物的制备进行了条件优化,确定了最佳反应路线,同时还通过熔点、核磁共振氢谱和碳谱对目标产物进行了表征.此合成方法为含多官能化苯乙胺结构的药物分子的合成提供了一种便利途径.     

Experimental study on inhibition of low pressure premixed flat methane-oxygen flames by trifluoromethane

This paper presents measurements of combustion species of low pressure laminar premixed flat methane-oxygen flames inhibited by triflnoromethane （CF3H） using synchrotron radiation-molecular beam mass spectrometry （SR-MBMS）. Fire suppression chemistry of CF3H is investigated by selective detection of combustion radicals and intermediates. Results show that SR-MBMS offers a powerful tool for studying fire suppression chemistry of halon replacements, which may extensively detect combustion species in the inhibited flames, especially radicals and intermediates. The suppressant CF3H is completely consumed in the preheat zone of premixed flames and produces fluorinated radicals such as CF3 and CF2. CF3 is the main radical participating in flame inhibition cycles in the reactive zone.Unlike HBr, HF produced by CF3H is very stable and will not act as a radical scavenger because the bond energy of H-F is much higher than that of H-Br, which is responsible for less effectiveness than conventional bromine-based suppressants.     

加强天然药物化学理论教学培养创造性思维

天然药物化学是高等医学院校药学专业的一门必修课,在教学中结合天然药物化学的课程特点,通过介绍天然药物发展史、改变教学模式、介绍新成果等方式,加强天然药物化学的理论教学,培养学生的创造性思维。     

Synthetic Application of Indium Hydride

1 Results Recently much interest was focused on the indium chemistry. Barbier and, Reformatsky types of reactions are main streams of the chemistry. The synthetic application of indium hydride (HInCl2), however, has been just started in contrast to the chemistry of the same 13th group of elements such as aluminum and boron hydrides. At first we generated the hydride by the transmetallation between Bu3SnH and InCl3, and then found it has both considerable stability and reactivity, and the hydride could b...     

治疗NSCLC的EGFR靶向性药物设计与筛选

计算了现有的治疗非小细胞肺癌(NSCLC)常见药物的相关参数,总结了以表皮生长因子受体(EGFR)酪氨酸激酶为靶标的药物分子的药效团特征.在Gefitinib的基础上进行了药物分子的组合化学设计,通过虚拟筛选得到了分子对接得分较高的结构分子,并对其进行了预测和模拟.结果表明:新设计筛选出的2种分子在药代动力学和毒性方面...     

过渡金属硫族化物纳米片的制备与生物应用

过渡金属硫族化物（TMDCs）是一类类石墨烯材料，具有高近红外吸收率，因此常被用作肿瘤光热治疗（PTT）过程中的光热剂以及光声成像（PAI）中的造影剂.TMDCs大多数情况下以二维纳米片的形式存在，具有更大的比表面积和更多的活性位点，可以通过负载不同功能的纳米小颗粒、药物小分子或生物大分子来赋予材料更多的可能性.文章主要介绍了TMDCs的合成与修饰，总结了常用的几种合成方法及其优缺点，以及该纳米材料在肿瘤诊疗中的一些应用.     

Enzymes for chemical synthesis

New catalytic synthetic methods in organic chemistry that satisfy increasingly stringent environmental constraints are in great demand by the pharmaceutical and chemical industries. In addition, novel catalytic procedures are necessary to produce the emerging classes of organic compounds that are becoming the targets of molecular and biomedical research. Enzyme-catalysed chemical transformations are now widely recognized as practical alternatives to traditional (non-biological) organic synthesis, and as convenient solutions to certain intractable synthetic problems.     

Chemical and biological research of Clematis medicinal resources

Clematis is a botanical source for various pharmaceutically active components,which has long been used in conventional medicine since the beginning of Chinese civilization.Increasing interest in Clematis medicinal resources has led to additional discoveries of triterpenoid saponins,flavonoids,coumarins,alkaloids and many other compounds in various Clematis species,and to investigations on their chemotaxonomy,molecular phylogeny and pharmacology.In continuation with our studies on Clematis chemistry and biology,we review the chemistry,chemotaxonomy,molecular biology and phylogeny of Clematis and their relevance to drug efficacy and drug development.Various databases and technology have been used in literature search in order to characterize the global scientific effort.It is essential to study more species for both the sustainable utilization of Clematis medicinal resources and finding novel compounds with potential clinical utility.Systems biology and omics technologies will play an increasingly important role in future medicinal research involving bioactive compounds of Clematis.     

环境因子影响三氯生对蝌蚪毒性作用研究

针对环境中残留的医药品在不同条件下对水生环境生物的毒性变化,选取水体pH值、水温、紫外线照射3种环境因子为评价因子,分别研究三氯生对环境生物东北林蛙幼体蝌蚪的急性毒性作用。结果显示,温度升高时,源于药物毒理动力学的改变和试验生物新陈代谢的加速,三氯生对蝌蚪毒性增大;由于在酸性条件下,不带电的分子态三氯生百分比相对碱性条件下更高,更易透过生物膜,继而产生生物毒性,导致在较低pH条件下三氯生毒性较大;在紫外线照射条件下三氯生对蝌蚪的Lc50较避光条件下有明显降低,表明在紫外线下三氯生光降解产物较母体毒性高。     

Crystal structure of human cytochrome P450 2C9 with bound warfarin

Cytochrome P450 proteins (CYP450s) are membrane-associated haem proteins that metabolize physiologically important compounds in many species of microorganisms, plants and animals. Mammalian CYP450s recognize and metabolize diverse xenobiotics such as drug molecules, environmental compounds and pollutants. Human CYP450 proteins CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are the major drug-metabolizing isoforms, and contribute to the oxidative metabolism of more than 90% of the drugs in current clinical use. Polymorphic variants have also been reported for some CYP450 isoforms, which has implications for the efficacy of drugs in individuals, and for the co-administration of drugs. The molecular basis of drug recognition by human CYP450s, however, has remained elusive. Here we describe the crystal structure of a human CYP450, CYP2C9, both unliganded and in complex with the anti-coagulant drug warfarin. The structure defines unanticipated interactions between CYP2C9 and warfarin, and reveals a new binding pocket. The binding mode of warfarin suggests that CYP2C9 may undergo an allosteric mechanism during its function. The newly discovered binding pocket also suggests that CYP2C9 may simultaneously accommodate multiple ligands during its biological function, and provides a possible molecular basis for understanding complex drug-drug interactions.     

Electrochemical dual-oxidation strategy enables access to α-chlorosulfoxides from sulfides

Electrochemistry contributes a strong tool for the manufacture of molecules,addressing intractable chal-lenges in synthetic chemistry by enabling innovative rea...     

Interconversion of single and double helices formed from synthetic molecular strands

Synthetic single-helical conformations are quite common, but the formation of double helices based on recognition between the two constituent strands is relatively rare. Known examples include duplex formation through base-pair-specific hydrogen bonding and stacking, as found in nucleic acids and their analogues, and polypeptides composed of amino acids with alternating L and D configurations. Some synthetic polymers and self-assembled fibres have double-helical winding induced by van der Waals interactions. A third mode of non-covalent interaction, coordination of organic ligands to metal ions, can give rise to double, triple and quadruple helices, although in this case the assembly is driven by the coordination geometry of the metal and the structure of the ligands, rather than by direct inter-strand complementarity. Here we describe a family of oligomeric molecules with bent conformations, which exhibit dynamic exchange between single and double molecular helices in solution, through spiral sliding of the synthetic oligomer strands. The bent conformations leading to the helical shape of the molecules result from intramolecular hydrogen bonding within 2'-pyridyl-2-pyridinecarboxamide units, with extensive intermolecular aromatic stacking stabilizing the double-stranded helices that form through dimerization.     

药用基础化学设计性实验的教学探索与实践

药用基础化学是药学专业的一门基础课程,设计性实验是医药类高职高专培养创新型人才的一条重要途径。文中以测定药物中残留溶剂的研究方法实验为例,分别从3个阶段详细阐述了在设计性实验教学过程中如何组织教学活动:实验准备阶段教师如何合理选题、如何引导学生初步设计实验方案、如何审查,实验实施阶段教师如何指导、学生如何开展实验;实验总结阶段如何形成科研小论文、怎样进行交流。同时探讨了开设设计性实验的意义和存在的问题。     

In vivo priming of virus-specific cytotoxic T lymphocytes with synthetic lipopeptide vaccine

Cytotoxic T lymphocytes (CTL) constitute an essential part of the immune response against viral infections. Such CTL recognize peptides derived from viral proteins together with major histocompatibility complex (MHC) class I molecules on the surface of infected cells, and usually require in vivo priming with infectious virus. Here we report that synthetic viral peptides covalently linked to tripalmitoyl-S-glycerylcysteinyl-seryl-serine (P3CSS) can efficiently prime influenza-virus-specific CTL in vivo. These lipopeptides are able to induce the same high-affinity CTL as does the infectious virus. Our data are not only relevant to vaccine development, but also have a bearing on basic immune processes leading to the transition of virgin T cells to activated effector cells in vivo, and to antigen presentation by MHC class I molecules.     

A combustion-free methodology for synthesizing zeolites and zeolite-like materials

Zeolites are mainly used for the adsorption and separation of ions and small molecules, and as heterogeneous catalysts. More recently, these materials are receiving attention in other applications, such as medical diagnosis and as components in electronic devices. Modern synthetic methodologies for preparing zeolites and zeolite-like materials typically involve the use of organic molecules that direct the assembly pathway and ultimately fill the pore space. Removal of these enclathrated species normally requires high temperature combustion that destroys this high cost component, and the associated energy release in combination with the formed water can be extremely detrimental to the inorganic structure. Here we report a synthetic methodology that avoids these difficulties by creating organic structure-directing agents (SDAs) that can be disassembled within the zeolite pore space to allow removal of their fragments for possible use again by reassembly. The methodology is shown for the synthesis of zeolite ZSM-5 using a SDA that contains a cyclic ketal group that is removed from the SDA while it is inside the zeolite without destruction of the inorganic framework. This approach should be applicable to the synthesis of a wide variety of inorganic and organometallic structures.     

钌催化1,6-烯炔环化反应的研究进展

五元环和六元环是许多药物及生物活性分子中的基本结构单元,广泛存在于各种天然产物中.因此,开发高效的合成方法构筑五元/六元环一直是有机合成的热点课题之一.其中,由于过渡金属钌(Ru)催化1,6-烯炔的环化反应具备原子经济、反应条件温和、对官能团兼容性好、产率和选择性高等特点,近年来得到了研究者的广泛青睐.基于反应机理及产物的多样性,简要综述了Ru催化1,6-烯炔环化反应的发展历程和最新进展.     

Integrating carbon-halogen bond formation into medicinal plant metabolism

Halogenation, which was once considered a rare occurrence in nature, has now been observed in many natural product biosynthetic pathways. However, only a small fraction of halogenated compounds have been isolated from terrestrial plants. Given the impact that halogenation can have on the biological activity of natural products, we reasoned that the introduction of halides into medicinal plant metabolism would provide the opportunity to rationally bioengineer a broad variety of novel plant products with altered, and perhaps improved, pharmacological properties. Here we report that chlorination biosynthetic machinery from soil bacteria can be successfully introduced into the medicinal plant Catharanthus roseus (Madagascar periwinkle). These prokaryotic halogenases function within the context of the plant cell to generate chlorinated tryptophan, which is then shuttled into monoterpene indole alkaloid metabolism to yield chlorinated alkaloids. A new functional group-a halide-is thereby introduced into the complex metabolism of C. roseus, and is incorporated in a predictable and regioselective manner onto the plant alkaloid products. Medicinal plants, despite their genetic and developmental complexity, therefore seem to be a viable platform for synthetic biology efforts.     

紫外老化对沥青化学组成与分子结构的影响

为研究紫外老化对沥青微观结构的影响,本文通过对四种沥青分别进行四组分、红外光谱和核磁共振等试验,研究了紫外老化下沥青的四组分、特征峰、官能团等化学组成指标和氢谱图、碳谱图、氢原子含量、分子结构参数等分子结构指标的变化,并通过分子结构指标对化学组成指标的表征,分析了分子结构变化对沥青化学组成变化的影响。结果表明:紫外老化后沥青更趋于形成沥青质分子,而沥青质的转化来源主要为芳香分,且含量越高老化后的损失率越高;同时羰基和亚砜基会随着老化的时间增加先快速增加之后趋于平缓,其中羰基指数可表征沥青老化的产生,而亚砜基指数可评价沥青抗老化的能力。紫外老化下沥青芳香环会发生缩合程度增大、环烷基取代基增加以及氢的取代、结构异化等反应;同时高紫外光子能量也会使脂肪碳发生断键,断键的脂肪碳连接到芳香环上提高了化学稳定性。由表征分析可见,沥青的化学组成主要受芳香结构、支化度和芳香环系缩合指数的影响较大。