Chelator

螯合剂
  • 文章类型: Journal Article
    硫代酰胺,它们是令人着迷的酰胺等排物,在药物发现和药物化学计划中获得了极大的关注,跨越肽和小分子化合物。这篇综述概述了硫代酰胺在针对一系列人类疾病的小分子治疗剂中的各种应用。包括癌症,微生物感染(例如,结核病,细菌,和真菌),病毒感染,神经退行性疾病,镇痛,和其他人。特别关注含生物活性硫代酰胺化合物及其生物靶标的设计策略,如激酶和组蛋白甲基转移酶ASH1L。此外,这篇综述讨论了硫代酰胺部分对关键性质的影响,包括效力,目标相互作用,物理化学特性,和药代动力学特征。我们希望这项工作将提供有价值的见解,以启发新型生物活性硫代酰胺化合物的未来发展,促进它们在对抗各种人类疾病中的有效使用。
    Thioamides, which are fascinating isosteres of amides, have garnered significant attention in drug discovery and medicinal chemistry programs, spanning peptides and small molecule compounds. This review provides an overview of the various applications of thioamides in small molecule therapeutic agents targeting a range of human diseases, including cancer, microbial infections (e.g., tuberculosis, bacteria, and fungi), viral infections, neurodegenerative conditions, analgesia, and others. Particular focus is given to design strategies of biologically active thioamide-containing compounds and their biological targets, such as kinases and histone methyltransferase ASH1L. Additionally, the review discusses the impact of the thioamide moiety on key properties, including potency, target interactions, physicochemical characteristics, and pharmacokinetics profiles. We hope that this work will offer valuable insights to inspire the future development of novel bioactive thioamide-containing compounds, facilitating their effective use in combating a wide array of human diseases.
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  • 文章类型: Journal Article
    背景:金属离子在调节各种生物系统中起着至关重要的作用,在实验过程中,必须控制溶液中游离金属离子的浓度。存在几种软件应用程序,用于在螯合剂存在的情况下估算游离金属的浓度。MaxChelator是该领域中易于访问的选择。这项工作旨在开发具有任意精度计算的Python版本的软件,广泛的新功能,和一个用户友好的界面来计算自由金属离子。
    结果:我们介绍了开源的PyChelatorWeb应用程序和基于Python的GoogleColaboratory笔记本,PyChelatorColab。主要功能旨在改善金属螯合剂计算的用户体验,包括较小单位的输入,在稳定常数之间进行选择,输入用户定义的常量,方便下载Excel格式的所有结果。这些功能是通过使用GoogleColab在Python语言中实现的,促进将计算器合并到其他基于Python的管道中,并邀请使用Python的科学家社区为进一步的增强做出贡献。通过使用内置的Decimal模块,采用了任意精度算法,以获得最准确的结果并避免舍入误差。与从PyChelatorweb应用程序获得的结果相比,没有观察到显著差异。然而,不同稳定常数来源的比较显示出它们之间的实质性差异。
    结论:PyChelator是一种用户友好的金属和螯合剂计算器,为进一步开发提供了平台。它作为交互式Web应用程序提供,免费使用在https://amrutelab。github.io/PyChelator,并在https://colab上作为基于Python的GoogleColaboratory笔记本。
    方法:google.com/github/AmruteLab/PyChelator/blob/main/PyChelator_Colab。ipynb.
    BACKGROUND: Metal ions play vital roles in regulating various biological systems, making it essential to control the concentration of free metal ions in solutions during experimental procedures. Several software applications exist for estimating the concentration of free metals in the presence of chelators, with MaxChelator being the easily accessible choice in this domain. This work aimed at developing a Python version of the software with arbitrary precision calculations, extensive new features, and a user-friendly interface to calculate the free metal ions.
    RESULTS: We introduce the open-source PyChelator web application and the Python-based Google Colaboratory notebook, PyChelator Colab. Key features aim to improve the user experience of metal chelator calculations including input in smaller units, selection among stability constants, input of user-defined constants, and convenient download of all results in Excel format. These features were implemented in Python language by employing Google Colab, facilitating the incorporation of the calculator into other Python-based pipelines and inviting the contributions from the community of Python-using scientists for further enhancements. Arbitrary-precision arithmetic was employed by using the built-in Decimal module to obtain the most accurate results and to avoid rounding errors. No notable differences were observed compared to the results obtained from the PyChelator web application. However, comparison of different sources of stability constants showed substantial differences among them.
    CONCLUSIONS: PyChelator is a user-friendly metal and chelator calculator that provides a platform for further development. It is provided as an interactive web application, freely available for use at https://amrutelab.github.io/PyChelator , and as a Python-based Google Colaboratory notebook at https://colab.
    METHODS: google.com/github/AmruteLab/PyChelator/blob/main/PyChelator_Colab.ipynb .
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  • 文章类型: Journal Article
    锌是许多缓冲液中普遍存在的污染物,纯化的产品和普通实验室器皿,以前曾被认为会影响功能性GlyR研究的结果,并且可能无意中导致某些GlyR调节剂的有效性被高估。这可能极大地影响潜在候选药物的评估,并导致达到临床阶段的化合物的有效性降低。由于在慢性疼痛病症期间观察到的脊髓锌浓度的变化,对于开发用于疼痛治疗剂的GlyR调节剂尤其如此。在这项研究中,我们使用双电极电压钳电生理学来评估金属螯合剂tricine和Ca-EDTA,并表明tricine对GlyRα1产生抑制作用,而该抑制作用不是由锌介导的。我们还利用锌不敏感的W170S突变作为工具来验证金属螯合剂并确认锌污染没有影响我们实验室先前开发的脂质调节剂的检查。这项研究有助于进一步开发方法,以消除污染锌在GlyRs功能研究中的影响,这些研究应纳入未来的研究中,以表征新型调节剂在GlyRs上的活性。
    Zinc is a ubiquitous contaminant in many buffers, purified products and common labware that has previously been suggested to impact on the results of functional GlyR studies and may inadvertently cause the effectiveness of some GlyR modulators to be over-estimated. This could greatly impact the assessment of potential drug-candidates and contribute to the reduced effectiveness of compounds that reach clinical stages. This is especially true for GlyR modulators being developed for pain therapeutics due to the changes in spinal zinc concentrations that have been observed during chronic pain conditions. In this study we use two-electrode voltage clamp electrophysiology to evaluate the metal chelators tricine and Ca-EDTA, and show that tricine produces inhibitory effects at GlyRα1 that are not mediated by zinc. We also utilized the zinc insensitive W170S mutation as a tool to validate metal chelators and confirm that zinc contamination has not impacted the examination of lipid modulators previously developed by our lab. This study helps to further develop methods to negate the impact of contaminating zinc in functional studies of GlyRs which should be incorporated into future studies that seek to characterize the activity of novel modulators at GlyRs.
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  • 文章类型: Journal Article
    许多微生物产生铁载体,这是一种非常强大的武器,能够从人体组织中窃取铁离子,液体和细胞,并通过其适当的孔将它们转移到细菌中。我们最近设计了一种多嵌段分子,每个块都有一个专门的角色。第一种成分是抗菌肽,通过交互式序列修饰,其对某些细菌菌株的良好效力逐渐提高。连接到这个块的是一个灵活的生物带,还优化了长度,终止于羟基酰胺单元,坚固的金属粘合剂。因此,整个分子汇集了两个协同作用对抗感染的部分。要了解肽单位,虽然用长尾巴修饰,保留了结构,因此保留了抗菌活性,并表征与模仿革兰氏阴性膜的生物膜模型相互作用的机制,我们进行了一系列基于荧光的实验和圆二色性研究,这进一步支持了我们设计两个不同实体协同工作的组合。通过铁(III)顺磁NMR分析证实了肽的螯合活性和铁(III)结合。并通过紫外可见光谱法与乙二胺-四乙酸进行竞争性测定。络合参数,米氏常数K,和站点数量n,这里报道的Fe(III)顺磁NMR分析证实了用分光光度技术评估。总之,我们表明,抗菌能力与铁捕获能力的结合在革兰氏阴性病原体引起的感染性疾病的治疗中效果良好。
    Many microbes produce siderophores, which are extremely potent weapons capable of stealing iron ions from human tissues, fluids and cells and transferring them into bacteria through their appropriate porins. We have recently designed a multi-block molecule, each block having a dedicated role. The first component is an antimicrobial peptide, whose good effectiveness against some bacterial strains was gradually improved through interactive sequence modifications. Connected to this block is a flexible bio-band, also optimized in length, which terminates in a hydroxyamide unit, a strong metal binder. Thus, the whole molecule brings together two pieces that work synergistically to fight infection. To understand if the peptide unit, although modified with a long tail, preserves the structure and therefore the antimicrobial activity, and to characterize the mechanism of interaction with bio-membrane models mimicking Gram-negative membranes, we performed a set of fluorescence-based experiments and circular dichroism studies, which further supported our design of a combination of two different entities working synergistically. The chelating activity and iron(III) binding of the peptide was confirmed by iron(III) paramagnetic NMR analyses, and through a competitive assay with ethylenediamine-tetra acetic acid by ultraviolet-visible spectroscopy. The complexation parameters, the Michaelis constant K, and the number of sites n, evaluated with spectrophotometric techniques are confirmed by Fe(III) paramagnetic NMR analyses here reported. In conclusion, we showed that the coupling of antimicrobial capabilities with iron-trapping capabilities works well in the treatment of infectious diseases caused by Gram-negative pathogens.
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  • 文章类型: Journal Article
    增强岩石风化(EW)是一种新兴的大气二氧化碳去除(CDR)策略,正在由商业部门扩大规模。这里,我们结合了地下微生物组的多组学分析,基于实验室的溶出度研究,以及现场EW试验对土壤的孵化研究,以建立操纵土壤中铁螯合剂以提高EW效率和降低成本的案例。微生物铁载体具有高亲和力,高选择性铁(Fe)螯合剂,可增强土壤矿物质中Fe的吸收。从EW田间试验对土壤和玄武岩颗粒应用RNA-seq元转录组学和shot弹元基因组学表明,玄武岩颗粒上的微生物群落相对于周围土壤的微生物组显着上调铁载体生物合成基因的表达。单独的体外实验室孵育研究表明,铁载体和高亲和力合成螯合剂的微摩尔溶液(乙二胺-N,N'-双-2-羟基苯乙酸,EDDHA)加速电子战以提高CDR速率。在这些发现的基础上,我们开发了一种潜在的生物技术途径,可以使用农学中常用的合成铁螯合剂EDDHA来加速EW,以减轻高pH土壤中的铁缺乏。通过促进玄武岩的非生物溶解和上调微生物铁载体的产生以进一步加速风化反应,用钾-EDDHA溶液孵育EW田间试验土壤将潜在的CDR率提高了2.5倍。此外,EDDHA可以缓解由于EW随时间升高的土壤pH而引起的作物的潜在铁限制。最初的成本效益分析表明,钾EDDHA可以将EW-CDR成本降低77美元/吨CO2ha-1,以提高EW相对于其他CDR策略的竞争力。
    Enhanced rock weathering (EW) is an emerging atmospheric carbon dioxide removal (CDR) strategy being scaled up by the commercial sector. Here, we combine multiomics analyses of belowground microbiomes, laboratory-based dissolution studies, and incubation investigations of soils from field EW trials to build the case for manipulating iron chelators in soil to increase EW efficiency and lower costs. Microbial siderophores are high-affinity, highly selective iron (Fe) chelators that enhance the uptake of Fe from soil minerals into cells. Applying RNA-seq metatranscriptomics and shotgun metagenomics to soils and basalt grains from EW field trials revealed that microbial communities on basalt grains significantly upregulate siderophore biosynthesis gene expression relative to microbiomes of the surrounding soil. Separate in vitro laboratory incubation studies showed that micromolar solutions of siderophores and high-affinity synthetic chelator (ethylenediamine-N,N\'-bis-2-hydroxyphenylacetic acid, EDDHA) accelerate EW to increase CDR rates. Building on these findings, we develop a potential biotechnology pathway for accelerating EW using the synthetic Fe-chelator EDDHA that is commonly used in agronomy to alleviate the Fe deficiency in high pH soils. Incubation of EW field trial soils with potassium-EDDHA solutions increased potential CDR rates by up to 2.5-fold by promoting the abiotic dissolution of basalt and upregulating microbial siderophore production to further accelerate weathering reactions. Moreover, EDDHA may alleviate potential Fe limitation of crops due to rising soil pH with EW over time. Initial cost-benefit analysis suggests potassium-EDDHA could lower EW-CDR costs by up to U.S. $77 t CO2 ha-1 to improve EW\'s competitiveness relative to other CDR strategies.
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  • 文章类型: Journal Article
    目标:目前,预混合腻子型生物陶瓷水泥(PPBC)已成为根端填料的流行材料。这项研究调查了使用PPBC和硅酸钙基密封剂(包括EDTA预处理)的三种根端填充技术。
    方法:用人工鳍和侧管制备并标准化了90个根节段,分为三组(n=30)。根端填充物单独使用BC-RRM腻子(PA组)放置,注入BC密封剂,然后是BC-RRM腻子(盖技术:LT组)或BC-RRM腻子与BC密封剂涂层(深腻子包装技术:DP组)。每组一半用17%EDTA预处理。通过五个等级的人评估样本的射线照相图像,并进行了推出粘结强度测试。用包括双向ANOVA和卡方检验的一般线性模型在5%的显著性水平下分析数据。
    结果:DP方法显示出明显高于LT的粘结强度(P<0.05)。然而,PA与DP或LT之间的粘结强度没有统计学上的显着差异。EDTA预处理对推出粘结强度没有显著影响。射线照相,对于主运河,PA和DP得分明显高于LT。在鳍上,PA评分明显高于其他评分(P<0.05)。
    结论:我们的研究强调了根端充填技术的变化。在放置PPBC之前注入大量生物陶瓷密封剂可能会降低粘合强度和射线不透性。单独或在深腻子技术中应用PPBC显示出有利结果的潜力。EDTA预处理没有增强粘结强度。
    结论:在根端填充中仔细选择和应用生物陶瓷材料和技术可能会影响牙髓根端手术的结果。当PPBC和硅酸钙基密封剂一起用于根端填充时,与盖子技术相比,密封剂随后使用深腻子可以提供改进的粘结强度和射线照相填充。
    OBJECTIVE: Currently, premixed putty-type bioceramic cements (PPBCs) have become popular materials for root-end fillings. This study investigated three root-end filling techniques using PPBCs and calcium silicate-based sealers including EDTA pretreatment.
    METHODS: Ninety root segments were prepared and standardized with an artificial fin and lateral canal, and assigned to three groups (n = 30). Root-end fillings were placed using BC-RRM Putty alone (Group PA), injection of BC sealer followed by BC-RRM Putty (Lid Technique: Group LT) or BC-RRM Putty with BC sealer coating (Deep putty packing technique: Group DP). Half of each group was pretreated with 17% EDTA. The radiographic images of the specimens were assessed by five graders and push-out bond strength tests were conducted. The data were analyzed with a general linear model including two-way ANOVA and chi-square test at a significance level of 5%.
    RESULTS: DP approach demonstrated significantly higher bond strength than LT (P < 0.05). However, there was no statistically significant difference in bond strength between PA and either DP or LT. EDTA pretreatment had no significant effect on push-out bond strength. Radiographically, for the main canal, PA and DP scored significantly higher than LT. In the fin, PA scored significantly higher than others (P < 0.05).
    CONCLUSIONS: Our study highlights variations in root-end filling techniques. Injecting a bulk of bioceramic sealer before the placement of PPBCs may reduce bond strength and radiopacity. The application of PPBCs alone or in the deep putty technique demonstrates potential for favorable outcomes. EDTA pretreatment did not enhance bond-strength.
    CONCLUSIONS: Careful selection and application of bioceramic materials and techniques in root-end fillings may influence the outcome of endodontic root-end surgery. When PPBCs and calcium silicate-based sealers are used together for root-end fillings, sealer followed by deep putty application may offer improved bond strength and radiographic fill compared to the lid technique.
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  • 文章类型: Journal Article
    一种新型的二硼酸盐笼形(笼形)配体,具有九个向内指向的氮供体,形成一个大的,刚性空腔,被称为毛索,是presented。腔的大小和高的凹度使其成为核医学中大型放射性核素的有吸引力的输送工具。金属盐络合物对空气和水(中性pH)是稳定的,并显示极高的热稳定性(>400°C)。在室温下,mausolate配体对镧系元素的吸收在溶液中迅速发生,一旦络合,在超过一周的时间内,镧系元素离子不会被250倍过量的竞争性镧系元素盐取代。
    A new type of diborate clathrochelate (cage) ligand featuring nine inwardly pointing nitrogen donors that form a large, rigid cavity, termed a mausolate, is presented. The cavity size and high denticity make this an attractive delivery vehicle for large radionuclides in nuclear medicine. Metal mausolate complexes are stable to air and water (neutral pH) and display extremely high thermal stability (>400 °C). Lanthanide uptake by the mausolate ligand occurs rapidly in solution at room temperature and once complexed, the lanthanide ions are not displaced by a 250-fold excess of a competitive lanthanide salt over more than one week.
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  • 文章类型: Journal Article
    来自城市固体废物焚化炉(MSWIs)的粉煤灰含有大量具有高浸出毒性的重金属,造成有害的环境影响。粉煤灰中的Pb2+是最有可能超过允许水平的离子。然而,化学稳定方法显示在酸性条件下稳定Pb2+的效果差。在这里,我们开发了一种坚固的耐酸螯合聚合物(25DTF),用于增强粉煤灰中Pb2的稳定性。通过甲醛与2,5-二硫脲的反应合成了25DTF。25DTF显示出显著的螯合效率,接近100%,粉煤灰中的Pb2+。25DTF表现出优异的螯合效率,超过99.9%,在pH≤7时与粉煤灰中的Pb2+相互作用。即使在酸性条件下,25DTF有效阻止了Pb2+的二次溶解。此外,它表明在中国不同地区具有出色的Pb2+螯合效率。25DTF螯合剂在减轻土壤中金属离子污染方面显示出相当大的潜力,废水,和城市环境管理,从而促进环境管理方面的进步。
    Fly ash derived from municipal solid waste incinerators (MSWIs) harbors significant quantities of heavy metals with high leaching toxicity, resulting in detrimental environmental effects. Pb2+ in fly ash is the ion most likely to exceed permissible levels. However, chemical stabilization methods demonstrate poor efficacy in stabilizing Pb2+ under acidic conditions. Herein, we have developed a robust acid-resistant chelating polymer (25DTF) for enhanced stabilization of Pb2+ in fly ash. 25DTF was synthesized through the reaction of formaldehyde with 2,5-dithiourea. 25DTF exhibited remarkable chelation efficiency, nearing 100%, for Pb2+ in fly ash. 25DTF demonstrated exceptional chelation efficiency, surpassing 99.9%, when interacting with Pb2+ in fly ash at pH ≤ 7. Even under acidic conditions, 25DTF effectively prevented the secondary dissolution of Pb2+. Additionally, it indicated outstanding Pb2+ chelation efficiency across diverse regions of China. The 25DTF chelating agent shows considerable potential in alleviating metal ion contamination in soil, wastewater, and urban environmental management, thereby fostering advancements in environmental stewardship.
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  • 文章类型: Journal Article
    铁和铜螯合疗法在治疗与金属过载相关的疾病中起着至关重要的作用,如血色素沉着症或威尔逊病。然而,传统的螯合剂在到达铁和铜代谢的核心-线粒体方面面临挑战。线粒体靶向螯合剂可以特异性靶向和去除线粒体中的金属离子,在治疗与线粒体功能障碍有关的疾病方面显示出希望,包括神经退行性疾病和癌症。此外,它们作为特定的线粒体金属传感器。然而,设计这些新分子提出了自己的一系列挑战。根据螯合剂防止或促进金属氧化还原循环的预期用途,螯合部分必须具有不同的供体原子和螯合剂-金属络合物的电极电位的最佳值。各种靶向部分可用于选择性递送到线粒体中。本文还概述了线粒体靶向螯合剂的设计及其生物学活性研究的最新进展。
    Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson\'s disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism - the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator\'s intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator-metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation.
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  • 文章类型: Journal Article
    据报道,堆肥中单独添加磁铁矿(MGT)会产生OH。然而,添加次氮基三乙酸(NTA)用于磁铁矿改良污泥堆肥的潜力尚不清楚。研究了三种不同添加量的处理[对照检查(CK);T1:5%MGT;T2:5%MGT+5%NTA]以表征羟基自由基,腐殖质和细菌群落反应。NTA添加表现出最佳性能,通过促进Fe(Ⅱ)/Fe(Ⅲ)的循环,OH含量增加了52%。导致最高的有机物降解(22.3%)和腐殖酸含量(36.1g/kg)。此外,NTA添加改变了细菌群落反应,促进铁-氧化还原相关属的相对丰度,和氨基酸代谢,但减少碳水化合物代谢。结构方程模型表明,温度和链霉菌是影响OH含量的主要因素。研究表明,利用螯合剂是一种有前途的策略,可以通过添加含铁矿物来加强污水污泥堆肥中的腐殖化。
    The OH production by adding magnetite (MGT) alone has been reported in composting. However, the potential of nitrilotriacetic acid (NTA) addition for magnetite-amended sludge composting remained unclear. Three treatments with different addition [control check (CK); T1: 5 % MGT; T2: 5 % MGT + 5 % NTA] were investigated to characterize hydroxyl radical, humification and bacterial community response. The NTA addition manifested the best performance, with the peak OH content increase by 52 % through facilitating the cycle of Fe(Ⅱ)/Fe(Ⅲ). It led to the highest organic matters degradation (22.3 %) and humic acids content (36.1 g/kg). Furthermore, NTA addition altered bacterial community response, promoting relative abundances of iron-redox related genera, and amino acid metabolism but decreasing carbohydrate metabolism. Structural equation model indicated that temperature and Streptomyces were the primary factors affecting OH content. The study suggests that utilizing chelators is a promising strategy to strengthen humification in sewage sludge composting with adding iron-containing minerals.
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