Reactions of Phosphorus Sulfides with Organophosphorus Substances

Abstract

We have found that the reactions of P4SIo and 1,3,2,4-dithiadiphosphetane-2,4-disulfides with phosphites, phosphonites, phosphinites, amidophosphonites, amidophosphinites, trithiophosphites, dithiophosphonites and thiophosphinites proceed under mild conditions via the previous formation of products containing the P(S)-S-P structural fragment which were isolated by column chromatography.     

Copper‐Chelating Azides for Efficient Click Conjugation Reactions in Complex Media

The concept of chelation‐assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)‐catalyzed azide–alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper‐chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.     

Investigating Ugi/Passerini Multicomponent Reactions for the Site-Selective Conjugation of Native Trastuzumab**

Site-selective modification of proteins has been the object of intense studies over the past decades, especially in the therapeutic field. Prominent results have been obtained with recombinant proteins, for which site-specific conjugation is made possible by the incorporation of particular amino acid residues or peptide sequences. In parallel, methods for the site-selective and site-specific conjugation of native and natural proteins are starting to thrive, allowing the controlled functionalization of various types of amino acid residues. Pursuing the efforts in this field, we planned to develop a new type of site-selective method, aiming at the simultaneous conjugation of two amino acid residues. We reasoned that this should give higher chances of developing a site-selective strategy compared to the great majority of existing methods that solely target a single residue. We opted for the Ugi four-centre three-component reaction to implement this idea, with the aim of conjugating the side-chain amine and carboxylate groups of two neighbouring lysine and aspartate/glutamate. Herein, we show that this strategy can give access to valuable antibody conjugates bearing several different payloads; furthermore, the approach limits the potential conjugation sites to only six on the model antibody trastuzumab.     

通过皮肤吸收的砷中毒病例观察

测定了７０例皮肤接触砷（Ａｓ）引起中毒症状的患者血清砷、谷丙转氨酶（ＡＬＴ）、白细胞总数（ＷＢＣ）及分类（ＤＣ）计数，结果显示患者除出现严重皮肤溃烂的临床症状外，血中嗜中性粒细胞明显增高，均值高于正常对照组，Ｐ〈０．０１；血清砷含量均值为０．４２μｍｏｌ／Ｌ，显著高于正常对照组（ｘ↑－〈０．０１μｍｏｌ／Ｌ），Ｐ〈０．０１。说明人体皮肤对砷有很强的吸收能力，应尽量防止皮肤接触引起的类似中毒事件发生     

Study of Fluoroapatite Reactions: The Effect of Metaphosphate Melts on Fluorine-Containing Substances

Abstract

The interaction of metaphosphate melts with fluorine-containing substances was studied. The major variables were composition and temperature. Sodium metaphosphate in contact with fluorides or fluoroapatite gives rise to reactions above 550°C, which liberate fluorine in the form of volatile compounds, mostly as hydrogen fluoride. At least one gas containing phosphorus and fluorine is released from. the melt. Evidence points to phosporyl trifluoride (POF₃). The relative amcunt of HF to POF₃ depends on the concentration of combined hydrogen in the melt and water vapor in the atmosphere above the melt. The rate of the removal of the gaseous reaction products is markedly affected by the depth of the layer through which they have to diffuse. The interaction of metaphosphate melts with fluorides is a general reaction independent of the type of fluoride, and produces the same major products in the gaseous phase. Calcium ions are more effective in furthering the gas evolution from the melt than sodium ions. The structure of synthetic fluoroapatite is destroyed by sodium metaphosphate above 550°C, and under certain conditions the fluorine content of the sample is reduced by 80% within an hour. The yield in the fluorine-containing gases shows a maximum at about 640°C.     

Conjugation of indole derivatives by copper-catalyzed alkyne-azide cycloaddition

An efficient synthetic procedure to combine biologically active indole derivatives by the triazole-containing spacer in a molecule has been proposed. The procedure was based on a copper-catalyzed alkyne-azide cycloaddition of azide-containing carbazoles and N-propargyl-containing carbazoles, tetrahydrocarbazoles, and tetrahydro-γ-carbolines.     

Solid State Reactions of Hemin with Basic Substances: Formation of bis and Mixed Complexes

The solid state reactions of hemin with KCN, Na₂SxH₂O, arginine, imidazole, 1-methylimidazole, 2-methylimidazole, benzimidazole, and mixtures of these basic reagents were monitored using IR, Mössbauer, and XRD techniques. All these basic substances react at the peripheral propionic acid group of hemin-forming salts. Binary mixtures of KCN, arginine, imidazole, 1-methylimidazole, 2-methylimidazole, and benzimidazole were found to form complexes with mixed ligands at the iron site of hemin. According to the structural information obtained for these mixed complexes, mechanisms for their formation are proposed. The solid state synthesis and the properties of the obtained products reveal the specifities of the involved ligands.     

Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides

Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site‐specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000‐fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d ‐Ala‐d ‐Ala revealed a mode of action beyond inhibition of cell‐wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.     

Conjugation of aminoadamantanes by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition

Four variants of conjugation of aminoadamantanes with 1,2,3-triazole- and ditriazolecontaining spacers by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of azido- and propargyl-containing aminoadamantanes were suggested.     

Enhancing the Activity of Drugs by Conjugation to Organometallic Fragments

Resistance to chemotherapy is a current clinical problem, especially in the treatment of microbial infections and cancer. One strategy to overcome this is to make new derivatives of existing drugs by conjugation to organometallic fragments, either by an appropriate linker, or by direct coordination of the drug to a metal. We illustrate this with examples of conjugated organometallic metallocene sandwich and half-sandwich complexes, Ru^II and Os^II arene, and Rh^III and Ir^III cyclopentadienyl half-sandwich complexes. Ferrocene conjugates are particularly promising. The ferrocene–chloroquine conjugate ferroquine is in clinical trials for malaria treatment, and a ferrocene-tamoxifen derivative (a ferrocifen) seems likely to enter anticancer trails soon. Several other examples illustrate that organometallic conjugation can restore the activity of drugs to which resistance has developed.     

Evaluation of polymorphisms in repair and detoxification genes in alcohol drinkers and non-drinkers using capillary electrophoresis

Alcohol use disorder (AUD) causes about 3.3 million deaths around the world each year. It is the primary risk factor for the global burden of diseases in American countries. Long-term abuse of alcohol induces numerous molecular and biochemical changes in tissues exposed to alcohol. The toxic effects of alcohol are mediated by DNA damage through various mechanisms, such as induction of oxidative damage, DNA adducts, crosslinks, and DNA strand breaks. The main aim of the current study was to compare the frequency of SNP polymorphisms in XRCC1 (rs7997782) and GSTP1 (rs1695) genes involved in DNA repair of single strand breaks (SSB) and xenobiotic detoxification between alcohol addicts and a control group comprised of non-drinkers. Genetic polymorphisms were identified following allelic specific PCR designed to generate the amplicons containing the variants. Then amplicons were sequenced, and sequences were aligned against the human genome reference deposited in GenBank using the CLC Sequence Viewer software (version 7.6.1). The GG homozygotes in rs1695 (GSTP1) were significantly (p = 0.023) 3.8x more frequent among those with AUD when compared to the control group. No SNP variation was observed in rs7997782 (XRCC1). rs1695 variant has been associated with susceptibility to various diseases, including those related to alcohol consumption.     

聚合物蛋白质类药物单分子修饰的发展和展望

随着基因组学、生物化学、分子生物学及多肽合成等科学技术的发展,蛋白质及多肽药物已成为跨国医药企业竞相争夺未来生物医药领域的一个制高点。但是蛋白质类药物的临床应用受到了其理化及生物特性的种种限制,为了改善治疗效果,近年来聚合物修饰的蛋白质类药物有了长足的发展。本文着重回顾了蛋白质类药物聚乙二醇修饰的发展和现状,以及由此获得的优点和局限性;同时介绍了其它新型生物相容性聚合物蛋白质类药物修饰的最新研究进展,探讨了蛋白质类药物的"后聚乙二醇修饰"时代的可能方向和应用前景。     

Conjugation of 1-Aminoadamantanes and 5-Trifluoromethylhydantoins by 1,3-Dipolar Cycloaddition

Russian Journal of General Chemistry - A synthetic approach was proposed for combining pharmacophore scaffolds, namely, 1-aminoadamantanes and 5-trifluoromethylhydantoins by the copper-catalyzed...     

Functional Stabilization of Cellulase from Aspergillus niger by Conjugation with Dextran-aldehyde

The covalent conjugates of cellulase from Aspergillus niger were prepared with various molar ratios by using dextran. The conjugate (n_E/n_D: 1/5) showed higher activity than purified enzyme at all temperatures after 1 h of incubation and its activity could also be measured at higher temperature. Also, this conjugate lost only 60% activity in 2 h at 70°C in comparison to the purified enzyme, which lost all its activity. In addition, conjugation protected cellulase against denaturation in the presence of sodium dodecylsulfate (residual activity of about 80%) and inactivation by air bubbles (residual activity of about 50% for 4 h).     

液质联用分析美伐他汀的有关物质

美伐他汀(mevastatin,结构见图1)是肝脏合成胆固醇的限速酶--羟甲基戊二酸单酰辅酶A(HMG-CoA)还原酶抑制剂,对体内降低胆固醇有积极作用,它的一种衍生物--普伐他汀在降低胆固醇方面有更强的药性,因而美伐他汀被作为生产普伐他汀的原料.     

Analysis of Atorvastatin and Related Substances by MEKC

A new micellar electrokinetic capillary chromatographic (MEKC) method has been developed for simultaneous quantitation of atorvastatin (AT) and its related substances. The separation was carried out in an extended light path capillary at applied voltage of 30 kV using a background electrolyte consisting of 10 mM sodium tetraborate buffer pH 9.5, 50 mM sodium dodecyl sulphate and 20% (v/v) methanol. The addition of methanol to the running buffer resulted in a very effective choice to achieve resolution between the peaks of charged substances adjacent to AT as well as the peaks of neutral drug-related substances. Linear calibration curves were established over the concentration range 100–1,200 μg mL^?1 for AT and 1.0–12.5 μg mL^?1 for related substances. The proposed MEKC procedure has been validated with respect to selectivity, precision, linearity, limits of detection, and quantitation, accuracy and robustness. The method has been successfully applied to the determination of AT and purity evaluation of bulk drug and formulated products.     

Hydrosilylation Reactions Catalyzed by Rhenium

Hydrosilylation is an important process, not only in the silicon industry to produce silicon polymers, but also in fine chemistry. In this review, the development of rhenium-based catalysts for the hydrosilylation of unsaturated bonds in carbonyl-, cyano-, nitro-, carboxylic acid derivatives and alkenes is summarized. Mechanisms of rhenium-catalyzed hydrosilylation are discussed.     

铝氟联合中毒暨铝引起少儿钙磷铁锌生物有效利用不良综合征

对某村普查筛出的铝氟联合中毒病人及高氟,高氟铝、高铝的实验种鸡进行动态研究。结果表明,氟含量〉４０＊１０＾－６的主食玉米促成了一般摄铝浓度人群的铝吸收和蓄积,饲铝超过一般浓度１－４倍的童鸡便有肝、肾铝蓄积、骨铝反而显著下降,但均出现低龄人群和实验动物的高钙血和高骨矿性骨营养不良软化,高全血磷的ＡＴＰ生成减少,全血铁增高的缺铁性小细胞性贫血,低锌症,智能和体能下等钙磷铁锌生物有 良和低素质综合症,随