Convenient synthesis of (triphenyl)germyl and (triphenydstannyl substituted allenes

Allenyl-germanes and -stannanes, Ph₃MC(R)CCR′R″ (M = Ge, Sn) can be obtained, generally in excellent yield, through alkylcopper(I)-induced 1,3-substitution of the propargylic chlorides Ph₃MCCCR′R″Cl. In the tin series, however transmetallation is the main process when MeCu, H₂CCHCu or PhCu are used. The allenyl compounds in which R is (trimethylsilyl)ethynyl or 4,4-dimethyl-1,2-pentadienyl can be obtained by using the organozinc compounds instead of the copper(I) compound and using tetrakis(triphenylphosphine)palladium as catalyst.     

4个新型有机磷缩合试剂的合成及其在生物活性肽合成中的应用

报道了4个新型有机磷化合物：N-二乙氧基磷酰苯并唑酮(DEPBO)、N－(2-氧-1,3,2-二氧杂磷杂环乙烷基)-苯并唑酮(DOPBO)、3－(2'-氧-1',3',2'-二氧杂磷杂环己烷基)-氧-1,2,3-苯共三嗪-4(3H)-酮(DOPBT)和3－(二乙氧基磷酰基)-氧-1,2,3-苯并三嗪-4(3H)-酮(DEPBT)的合成,并研究了它们作为缩会试剂在多肽合成中的应用. 研究结果表明,它们可以成功地用于固相法和溶液法合成多肽,其中DEPBT还可用于环肽的合成. 应用DEPBO和DEPBT合成了促睡眠肽的类似物及从云南中草药繁缕中分离鉴定的一个环七肽等生物活性肽.     

Convenient one-pot formation of highly functionalized 5-bromo-2-aminothiazoles,potential endocannabinoid hydrolase MAGL inhibitors

Highly functionalized 5-bromo-2-amino-1,3-thiazoles bearing various substituents could be easily prepared by a rapid and efficient one-pot method, using simple starting materials and mild conditions while avoiding the use of metal catalysts or inconvenient reagents such as elemental halogens. These useful products can serve as starting materials for other reactions or as pharmacologically interesting compounds. In our work we have shown that the resulting 5-bromothiazole compounds could lead to monoacylglycerol lipase (MAGL) inhibition in the μM range.     

Statistical methodology for the detection of small changes in distances by EXAFS: application to the antimalarial ruthenoquine

Antimalarial compounds ruthenoquine and methylruthenoquine were studied by X-ray absorption spectroscopy both in solid state and in solution, in normal (aqueous or CH(2)Cl(2) solutions) and oxidative (aqueous solution with H(2)O(2), either equimolar or in large excess) conditions, to detect small changes in the coordination sphere of the ruthenium atom. Since changes in the EXAFS spectra of these compounds are quite subtle, a complete procedure was developed to assess the different sources of uncertainties in fitted structural parameters, including the use of multivariate statistic methods for simultaneous comparison of edge energy correction ΔE(0) and distances, which can take into account the very strong correlation between these two parameters. Factors limiting the precision of distance determination depend on the recording mode. In transmission mode, the main source of uncertainty is the data reduction process, whereas in fluorescence mode, experimental noise is the main source of variability in the fitted parameters. However, it was shown that the effects of data reduction are systematic and almost identical for all compounds; hence, they can be ignored when comparing distances. Consequently, for both fluorescence and transmission recorded spectra, experimental noise is the limiting factor for distance comparisons, which leads to the use of statistical methods for comparing distances. Univariate methods, focusing on the distance only, are shown to be less powerful in detecting changes in distances than bivariate methods making a simultaneous comparison of ΔE(0) and distances. This bivariate comparison can be done either by using the Hotelling's T(2) test or by using a graphical comparison of Monte Carlo simulation results. We have shown that using these methods allows for the detection of very subtle changes in distances. When applied to ruthenoquine compounds, it suggests that the implication of the nonbinding doublet of the aminoquine nitrogen in either protonation or methylation enhances the tilt of the two cyclopentadienyls. It also suggests that ruthenoquine and methylruthenoquine are, at least partially, oxidized in the presence of H(2)O(2), with a small decrease in the Ru-C bond length and increase in the edge energy.     

肟的无气味硫缩醛/酮化反应

探讨了以无气味且稳定的α-羰基二硫缩烯酮(1)作为代硫醇试剂的肟(2)的硫缩醛/酮化反应. 在乙酰氯-乙醇(体积分数95%)或4-十二烷基苯磺酸(DBSA)-水体系中及回流条件下, 化合物1与肟2能有效地进行硫缩醛/酮化反应. 反应过程中未闻到硫醇的恶臭气味.     

Versatile self-complexing compounds based on covalently linked donor-acceptor cyclophanes

A range of covalently linked donor-acceptor compounds which contain 1) a hydroquinone (HQ) unit, 2) a 1,5-dioxynaphthalene (DNP) ring system, or 3) a tetrathiafulvalene (TTF) unit as the pi-donor, and 4) cyclobis(paraquat-p-phenylene) (CBPQT(4+)) as the pi-accepting tetracationic cyclophane were prepared and shown to operate as simple molecular machines. The pi-donating arms can be included inside the cyclophane in an intramolecular fashion by virtue of stabilizing noncovalent bonding interactions. What amounts to self-complexing/decomplexing equilibria were shown to be highly temperature dependent when the pi-donating arm contains either an HQ or DNP moiety. The thermodynamic parameters associated with the equilibria have been unraveled by using variable-temperature (1)H NMR spectroscopy. The negative DeltaH degrees and DeltaS degrees values account for the fact that the "uncomplexed" conformation becomes the dominant species, since the entropy gain associated with the decomplexation process overcomes the enthalpy loss resulting from the breaking of the donor-acceptor interactions. The arm's in-and-out movements with respect to the linked cyclophanes can be arrested by installing a bulky substituent at the end of the arm. In the case of compounds carrying a DNP ring system in their side arm, two diastereoisomeric, self-complexing conformations are observed below 272 K in hexadeuterioacetone. By contrast, control over the TTF-containing arm's movement is more or less ineffective through the thermally sensitive equilibrium although it can be realized by chemical and electrochemical ways as a result of TTF's excellent redox properties. Such self-complexing compounds could find applications as thermo- and electroswitches. In addition, the thermochromism associated with the arm's movement could lead to some of the compounds finding uses as imaging and sensing materials.     

Isolation, characterization, and DNA binding kinetics of three dirhodium(II,II) carboxyamidate complexes: Rh2(μ-L)(HNOCCF3)3 where L= [OOCCH3]-, [OOCCF3]-, or [HNOCCF3]-

Several transition metal compounds are effective antitumor drugs whose biological activity can be attributed to their ability to bind deoxyribonucleic acid (DNA). In this study, DNA-binding experiments reveal that changing one bridging ligand on compounds with the general formula Rh(2)(μ-L)(HNOCCF(3))(3) alters the rate of DNA-binding by greater than 100-fold with μ-L = trifluoroacetate ? acetate > trifluoroacetamidate. These three dirhodium compounds are isolated as the major products of the reaction between Rh(2)(OOCCH(3))(4) and trifluoroacetamide in either refluxing chlorobenzene or molten trifluoroacetamide and have been characterized by NMR and LC/MS. By using (15)N-enriched trifluoroacetamide, NMR spectroscopy was used to assign the cis-(2,1) orientations of Rh(2)(μ-L)(HNOCCF(3))(3) compounds where μ-L = trifluoroacetate or acetate. This is the first report of Rh(2)(OOCCF(3))(HNOCCF(3))(3), a novel compound that may play a significant role in the biological and/or catalytic activity of compound mixtures commonly isolated as "Rh(2)(HNOCCF(3))(4)".     

Novel 4-vinylpyridine-extended metal-dibenzoylmethanate host frameworks: structure, polymorphism, and inclusion properties

In this contribution we show that host materials based on metal dibenzoylmethanates (DBM) can be extended in a versatile way by decreasing the packing efficiency of the simpler metal DBM's reported earlier. Specifically, this can be accomplished by coordinating two 4-vinylpyridines (4-ViPy) to the metal (Ni or Co) DBM units to give [M(4-ViPy)2(DBM)2] host complexes. These display a remarkable polymorphism and an ability to form inclusion compounds with a large variety of organic species. Five non-clathrate phases representing three polymorphic types and twenty-eight inclusion compounds with nineteen guests, representing five structural types were isolated and studied in varying degrees of detail. The inclusion compounds can be prepared by recrystallization or by interaction of the solid host with guest vapor. In the latter case, the process realization, kinetics and final product strongly depend on the host polymorph chosen as starting material. Kinetic studies executed with powder XRD suggest that transient formation of inclusion compounds may occur even during solvent vapor induced transformation of one guest-free polymorph to another. The beta polymorph of the Ni-host reveals the strongest clathratogenic ability as well as a high selectivity towards certain homologues and isomers. Its properties give insight into the concept of "flexible zeolite mimics", or "apohosts", as this empty host form is energetically and structurally predisposed towards inclusion processes. In all eleven (three host and eight clathrate) structures studied by single crystal X-ray diffraction the [M(4-Vi-Py)2(DBM)2] complex molecule is transconfigured. In most, the host molecules show effective packing in one dimension by forming parallel chains. Guest species are located between the chains in cages or channels formed by combining voids in the host molecules belonging to adjacent chains. The corresponding Ni and Co versions of the compounds studied were similar.     

Determination of Molybdenum in Steels, Soil, and Sea Water by Spectroscopic Methods and Adsorption Voltammetry

Procedures were developed for the determination of molybdenum in steels, soil, and sea water using o,o"-dihydroxyazo compounds [Lumogallion IREA (LG) and Magneson IREA (MG)] and heterocyclic azo compounds [4-(2-pyridylazo)resorcinol (PAR) and 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol (5-Br-PAAP)], including their determination in the presence of the third component, hydoxylamine (HA). The addition of the third component improved the selectivity of determination. The advantage of the developed procedures is that they do not involved extraction and, thus,shorten the analysis. Molybdenum can be determined in sea water in the presence of LG or LG + HA by diffuse reflectance spectroscopy or adsorption voltammetry using the added–found method or using visual tests. In the presence of MG, PAR, and 5-Br-PAAP, the standard addition method was used to eliminate the matrix effect.     

Development of generic liquid chromatography-mass spectrometry methods using experimental design

Standard approaches to development of liquid chromatography-mass spectrometry (LC-MS) methods, either ion-pairing or reversed-phase liquid chromatography, have been through trial and error or intentional variation of experimental factors. These approaches to method optimization fail to take into account interactions between experimental factors and therefore the results may not be optimal for the combination of experimental factors. Another approach to optimization is through the use of chemometrics. Chemometric approaches can be more efficient than trial and error or intentional variation because chemometrics make use of multivariate designs; experimental factors are varied simultaneously at the various levels. Therefore chemometrics can take into account interactions between factors. The goal of this study was to develop a generic ion-pair LC-MS method for the analysis of acidic compounds using a chemometric approach called design of experiments (DOE). Four acidic compounds which cover three classes of acidic functional groups: 1-naphthyl phosphate (1), 1-naphthalenesulfonic acid (2), 2-naphthalenesulfonic acid (3), and (1-naphthoxy)acetic acid (4) were used as model compounds to develop the generic method. This study illustrates that LC-MS conditions can be optimized efficiently with minimal amount of experimentation using a chemometric approach to experimental design.     

Rapid automated screening, identification and quantification of organic micro-contaminants and their main transformation products in wastewater and river waters using liquid chromatography-quadrupole-time-of-flight mass spectrometry with an accurate-mass database

In this study we have developed and evaluated an analytical method for a rapid automated screening and confirmation of a large number of organic micro-contaminants (almost 400) and also the quantification of the positive findings in water samples of different types (surface and wastewaters) using liquid chromatography-electrospray quadrupole-time-of-flight mass spectrometry (LC-QTOFMS) based on the use of an accurate-mass database. The created database includes data not only on the accurate masses of the target ions but also on the characteristic in-source fragment ions, isotopic pattern and retention time data. This customized database was linked to commercially available software which extracted all the potential compounds of interest from the LC-QTOFMS raw data of each sample and matched them against the database to search for targeted compounds in the sample. The detailed fragmentation information has also been used as a powerful tool for the automatic identification of unknown compounds and/or transformation products with similar structures to those of known organic contaminants included in the database. The database can be continually enlarged. To confirm identification of compounds which have no fragment ions (or fragments with low intensity/relative abundance) from in-source CID fragmentation or isomers which are not distinguished within full single mass spectra, a "Targeted MS/MS" method is developed. Thereafter, these compounds can be further analyzed using the collision energy (CE) in QTOF-MS/MS mode. Linearity and limits of detection were studied. Method detection limits (MDLs) in effluent wastewater and river waters were, in most cases, lowers or equal to 5 and 2 ng/L, respectively. Only 15 compounds had MDLs between 5 and 50 ng/L in effluent wastewater matrix. We obtained a linearity of the calibration curves over two orders of magnitude. The method has been applied to real samples and the results obtained reveal that most of the pharmaceutically active compounds contained in the created database were present in the water samples with concentrations in the range of ng/L and μg/L levels and in most of the samples between 2 and 15 pesticides of the 300 contained in the database were also detected. In addition to the compounds included in the database, some degradation products were found, thus revealing the method as a useful tool for the analysis of organic micro-contaminants in waters.     

液晶性芳香醛化合物的合成

以对羟基苯甲醛和对烷氧基联苯酰氯为原料,采用爱因宏反应,合成了一系列4-(4'-烷氧基联苯基-4-羧基)苯甲醛.化合物的结构通过元素分析、红外光谱、核磁共振和质谱等方法确证.化合物的液晶行为用示差扫描量热法、偏光显微镜和旋光仪等方法表征.结果表明,所有的化合物加热至各自的熔点以上都能形成液晶态.在液晶态可以观察到手性近晶C相、近晶相、胆甾相和向列相的典型织构.含手性中心的化合物都有较高的旋光性,而且在合成反应中旋光性得到保持.随着分子末端烷氧基碳原子数增加,化合物(除2a和4a外)的熔点(T_m)和液晶态的清亮点(T_i)呈规律性变化,近晶相范围和近晶相-向列相转变温度渐增,而向列相温度范围递减,至十二烷基时,仅呈现近晶性.     

Palladium-catalyzed alpha-arylation of esters

A new and simple one-pot procedure for the palladium-catalyzed intermolecular alpha-arylation of esters is described. A number of esters can be functionalized with a wide range of aryl bromides using Pd(OAc)(2) or Pd(2)(dba)(3) and bulky electron-rich o-biphenyl phosphines 1-3. Under the reaction conditions, using LiHMDS as base, alpha-arylation proceeds at room temperature or at 80 degrees C with very good yields and high selectivities for monoarylation. Important nonsteroidal antiinflammatory drug derivatives such as (+/-)-naproxen tert-butyl ester and (+/-)-flurbiprofen tert-butyl ester can be prepared in 79% and 86% yield, respectively. The catalyst system based on the di-tert-butylphosphine (2) is also active for the alpha-arylation of esters using aryl chlorides. Furthermore, using (3) the alpha-arylation of trisubstituted ester enolates can be accomplished to provide compounds that have quaternary centers.     

Elementary swelling and gelling theories

It has been experimentally illustrated that it is possible to form an n-phase thermodynamic system where n> or =2 and has a value which is limited by the properties of the system. For example, to attain limited chemical reversibility of a mineral matrix such as vermiculite using specific butyl ammonium vermiculite, it is necessary to reform chemical bonds using an additive and a particular ion. In other words, to obtain a similar thin film using exfoliated vermiculite as that obtained with natural vermiculite, hydrophobic or binding electrostatic bonds must be formed or reformed. It has also been observed that complementary structural compounds can be formed from other silicates, such as glycerine/sodium silicate. These compounds can also encase the vermiculite matrices. (Film Formation) is proportional to (A/Temp). (Pressure).(Ionic Content). Hence F=L(A/T)PE, where F=film formation, L=functional constant for the matrix compound, T=temperature, A=temperature constant, P=pressure, E=electrostatic force and P=force/area. Thus, F=LTE2 for unit area. SigmaF=pfL. TE2/SigmaPefl=F1, where P=the probability for film formation and SigmaPef(L) is the partition function for the film formation. This concept can be extended to a response geometric algorithm. This means that for every mineral matrix there is an algorithm to describe its formation or its response to an applied field. Thus deltasec2(E)tan(E1) is the response for (F1). V---, V1...Vn, F1...Fn1, ..., Fp, ...Fnp.     

Coated-wire organic ion-selective electrodes in titrations based on ion-pair formation: Part 2. Determination of ionic surfactants

Both cationic and anionic surfactants can be determined titrimetrically using a coated-wire electrode with a PVC membrane plasticized with 2-nitrophenyl 2-ethylhexyl ether. Cationic surfactants and other organic compounds of cationic character are titrated with sodium tetraphenylborate; for the titration of anionic compounds, cetylpyridinium bromide or 1-(ethoxycarbonyl)pentadecyl-trimethylammonium bromide (Septonex) is recommended. Characteristics of titration curves together with statistical evaluation of results are described for determinations of 15 specimens, involving pure substances as well as technical samples.     

A catalytic amount of nickel(II) chloride hexahydrate and 1,2-ethanedithiol is a good combination for the cleavage of tetrahydropyranyl (THP) and tert-butyldimethylsilyl (TBS) ethers

Various THP and TBS ethers can be unmasked easily to the corresponding hydroxyl compounds in good yields by using a combination of a catalytic amount of nickel(II) chloride hexahydrate and 1,2-ethanedithiol at room temperature. In addition, alkyl TBS ethers can be hydrolyzed chemoselectively in the presence of aryl TBS ethers. Moreover, alkyl TBS ethers can be cleaved easily in the presence of alkyl or aryl THP ethers using the same conditions.     

Using blood hemoglobin for blood analysis

This paper demonstrates that the spectrophotometric properties of blood hemoglobin (Hb) can be used for the direct determination of biochemical compounds in blood. Glucose is used as a model, but the methodology can be applied to many other compounds (only a previous enzymatic reaction producing H(2)O(2) is needed). In order to develop the method, a model relating the Hb absorbance variation during the reaction with the glucose concentration has been developed to provide theoretical support for the method and to predict its application to other compounds. In addition, clear blood samples need to be prepared without pre-treatment and lateral reactions of H(2)O(2) with other blood constituents need to be blocked; this has been achieved with 100 : 1 v/v blood dilution in bi-distilled water and azide addition. The linear response range of the method can be fitted between 2 and 540 mg dL(-1) glucose relative to the original blood sample (RSD about 4%, 70 mg dL(-1)). The analyte concentration can be obtained by an absolute calibration method or by the standard addition method; both have been applied for direct glucose determination in several blood samples and good correlations with those obtained by an automatic analyzer have been obtained.     

3D-QSAR study on heterocyclic topoisomerase II inhibitors using CoMSIA

Selective topoisomerase II (Topo II) inhibitors have interested to a great extent for the design of new antitumoral compounds in recent years. Comparative molecular similarity indices analysis (CoMSIA) was performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazolo(4,5-b)pyridine derivatives as eukaryotic Topo II inhibitors. A training set of 16 heterocyclic compounds was used to establish the CoMSIA model. They were constructed and geometrically optimized using SYBYL v7.0. The predictive ability of the model was assessed using a test set of 7 compounds. The best model has demonstrated a good fit having r2 value of 0.968 and cross-validated coefficient q2 value as 0.562 including steric and hydrophobic fields. The hydrophobic interactions showed a dominant role for increasing Topo II inhibitor activity and hydrophilic substituent was found more important than hydrophobic one on the 5 or 6 position of benzazole moiety. The model obtained from the present study can be useful for the modification and/or evaluation of the development of new Topo II inhibitors as potential antitumor compounds.     

Practical azidation of 1,3-dicarbonyls

An operationally simple, direct azidation of 1,3-dicarbonyl compounds has been developed. The reaction proceeds readily under ambient conditions using sodium azide and an iodine-based oxidant such as I(2) or 2-iodoxybenzoic acid (IBX)-SO(3)K/NaI. In particular, the latter method, as a new and well-balanced oxidizing agent, shows excellent functional group tolerance and substrate scope and thus allows access to a variety of tertiary 2-azido and 2,2-bisazido 1,3-dicarbonyl compounds that would be more difficult to access by using traditional methods. Because the azide-containing products easily undergo 1,3-dipolar cycloaddition with alkynes, our report represents a novel route to analogues of sensitive complex molecules.     

Computational validation of the importance of absolute stereochemistry in virtual screening

Consideration of stereochemistry early in the identification and optimization of lead compounds can improve the efficiency and efficacy of the drug discovery process and reduce the time spent on subsequent drug development. These improvements can result by focusing on specific enantiomers that have the desired potential therapeutic effect (eutomers), while removing from consideration enantiomers that may have no, or even undesirable, effects (distomers). A virtual screening campaign that correctly takes stereochemical information into account can, in theory, be utilized to provide information about the relative binding affinities of enantiomers. Thus, the proper enumeration of the relevant stereoisomers in general, and enantiomeric pairs in particular, of chiral compounds is crucial if one is to use virtual screening as an effective drug discovery tool. As is obvious, in cases where no stereochemical information is provided for chiral compounds in a 2D chemical database, then each possible stereoisomer should be generated for construction of the subsequent 3D database to be used for virtual screening. However, acute problems can arise in 3D database construction when relative stereochemistry is encoded in a 2D database for a chiral compound containing multiple stereogenic atoms but absolute stereochemistry is not implied. In this case, we report that generation of enantiomeric pairs is imperative in database development if one is to obtain accurate docking results. A study is described on the impact of the neglect of enantiomeric pairs on virtual screening using the human homolog of murine double minute 2 (MDM2) protein, the product of a proto-oncogene, as the target. Docking in MDM2 with GLIDE 4.0 was performed using the NCI Diversity Set 3D database and, for comparison, a set of enantiomers we created corresponding to mirror image structures of the single enantiomers of chiral compounds present in the NCI Diversity Set. Our results demonstrate that potential lead candidates may be overlooked when databases contain 3D structures representing only a single enantiomer of racemic chiral compounds.