Hole Migration in Telomere-Based Oligonucleotide Anions and G-Quadruplexes

Vacuum ultraviolet photoionization of a gas-phase oligonucleotide anion leads to the formation of a valence hole. This hole migrates towards an energetically favorable site where it can weaken bonds and ultimately lead to bond cleavage. We have studied Vacuum UV photoionization of deprotonated oligonucleotides containing the human telomere sequence dTTAGGG and G-quadruplex structures consisting of four dTGGGGT single strands, stabilized by NH₄⁺ counter ions. The oligonucleotide and G-quadruplex anions were confined in a radiofrequency ion trap, interfaced with a synchrotron beamline and the photofragmentation was studied using time-of-flight mass spectrometry. Oligonucleotide 12-mers containing the 5'-TTAGGG sequence were found to predominantly break in the GGG region, whereas no selective bond cleavage region was observed for the reversed 5'-GGGATT sequence. For G-quadruplex structures, fragmentation was quenched and mostly non-dissociative single and double electron removal was observed.     

QSAR Studies on the COX-2 Inhibition by 3,4-Diarylcycloxazolones Based on MEDV Descriptor

Selective inhibition of cyclooxygenase-2 (COX-2) might avoid the side effects of current available nonsteroidal antiinflammatory drugs while retaining their therapeutic efficacy. A novel variable selection and modeling method based on prediction is developed to construct the quantitative structure-activity relationships (QSAR) between the molecular electronegativity distance vector (MEDV) based on 13 atomic types and the biological activities of a set of selective cyclooxygenase-2 inhibitory molecules, 3,4-diarylcycloxazolones (DAA) plus indomethacin,naproxen, and celecoxib. Using multiple linear regression, a 5-variable linear model is developed with the calibrated correlation coefficient of 0.9271 and root mean square error of 0.17 in modeling stage and the validated correlation coefficient of 0.9030 and root mean square error of 0.20 in leave-one-out validation step, respectively. To further test the predictive ability of the model, 20 DAA compounds are picked up to construct a training set which is used to build a QSAR model and then the model is employed to predict the biological activities of the balance compounds. The predicted correlation coefficient and root mean square error are 0.9332 and 0.19, respectively.     

药物发现中常用化合物库特征描述与对比分析

随着计算技术的发展和分子模拟软件的日趋成熟, 虚拟筛选已经在药物发现过程中发挥着越来越重要的作用. 在虚拟筛选过程中, 所使用化合物库的质量对先导化合物发现的成功率起着至关重要的作用. 本文通过对已知药物库、天然产物库、中药原植物化学成分库、筛选常用商业化合物库以及研究者所在实验室建立的化合物库的分析比较, 从化合物库的分子多样性、化学空间和分子骨架等多个方面提取并对比每一种化合物库的特征, 发现了已知药物库与中药原植物化学成分库的特征相似性, 揭示了中药原植物化学成分库作为筛选库的类药性优势, 并且深化了对几种筛选用化合物库特征的认识和理解.     

Metal‐Free Oxidative Radical Addition of Carbonyl Compounds to α,α‐Diaryl Allylic Alcohols: Synthesis of Highly Functionalized Ketones

A metal‐free direct alkylation of simple carbonyl compounds (ketones, esters, and amides) with α,α‐diaryl allylic alcohols is described. The protocol provides facile access to highly functionalized dicarbonyl ketones by a radical addition/1,2‐aryl migration cascade. The regioselectivity of the reaction was precisely controlled by the nature of the carbonyl compound.     

Double‐injection capillary electrophoresis for the identification of analytes

This paper presents a new approach for identifying analytes by CE. The compound to be identified is analyzed together with the corresponding reference standard during a double injection capillary electrophoretic run. The inter‐plug distance is regulated by applying an electrical field over the capillary for a predetermined time period (t_PE). The migration time of an analyte being exposed to the partial electrophoresis was calculated from the partial migration time (t_mig(p)) as described in this paper. The identification is based on the closeness of agreement between the calculated migration time (t_mig(c)) and observed migration time (t_mig) of the reference standard. The validity of the derived equations was checked by analyzing several substances such as caffeine, melamine, acetyl salicylic acid, paracetamol, ibuprofen, metoprolol, naproxen, somatropin, several insulin analogs, as well as different pharmaceutical and natural products. The migration time ratios for the identified solutes varied between 0.996 and 1.006 (i.e., 1.001 ± 0.005), indicating good agreement between the observed and calculated migration times.     

Synthesis of aromatic tetracyclic tin compounds by template and transmetallation reactions: Alkyl vs aryl migration from tin to nitrogen

The syntheses of [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]diphenyltin (1) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]dichloro-phenyl-stannate (2) by template reactions using 3,5-di-tert-butylcatechol, aqueous ammonia and SnPh₂Cl₂ are reported. We also report the syntheses of compounds 2, [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]trichloro-stannate (4), [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)methylamine]chloro-methyltin (5), and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)-n-butylamine]n-butyl-chlorotin (6) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]n-butyl-dichloro-stannate (7), performed by transmetallation reactions of the octahedral zinc coordination compound Zn[3,5-di-tert-butyl-1,2-quinone-(3,5-di-tert-butyl-2-hydroxy-1-phenyl)imine]₂ (3) with SnPhCl₃ or SnPh₂Cl₂, SnCl₄, SnMe₂Cl₂, Sn(nBu)₂Cl₂ and Sn(nBu)Cl₃, respectively. The X-ray diffraction structures of compounds 1, 2, 4 and 6 are reported. The transmetallation reactions with Sn(alkyl)₂Cl₂ afforded pentacoordinated tin compounds, where an alkyl group migrated from tin to nitrogen, while similar reactions with Sn-Ph compounds did not present any phenyl group migration.     

Migration of Additives from Poly(vinyl chloride) (PVC) Tubes into Aqueous Media

The stability and migration product of medical PVC tubes plasticized with polyadipates were investigated by ageing in phosphate buffer at pH 1.679 and water at different temperatures. Changes in the PVC tubes were studied by water absorption, weight loss, Fourier infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). The low molecular weight migration product that was released was extracted and silylanized before gas chromatography/mass spectroscopy (GC/MS) identification and quantification. After 70 days, the weight loss was less than 0.5% and only a small amount of adipic acid migrated when a tube was aged at 37°C in water and phosphate buffer (pH 1.679), and at 70°C in water after 56 days. However, when aged at 70 and 110°C, gradual deactivation of heat stabilizer after 21 days of ageing in buffer solution and separation of plasticizer from PVC matrix occurred. When the tube was aged at 110°C, significant degradation of both polyadipates and PVC were observed. Adipic acid and 1,4-butanediol monomers and oligomers of polyadipate were the major migration products from polyadipates in the water ageing solution, while only a relatively high amount of adipic acid was identified as the main product in the buffer ageing solution.     

Reaction of a 5α-bromo-6β,19-epoxysteroid with BF3·Et2O/Ac2O: An evidence of a cyclic bromonium cation

Treatment of 3β-acetoxy-5-bromo-6β,19-epoxy-5α-androstan-17-one with Ac₂O and BF₃·OEt₂, produced the cleavage of the epoxy moiety and migration of the bromine atom to afford 3β,19-diacetoxy-6α-bromo-5-hydroxy-5β-androst-17-one in high yield.     

A new mechanism of nucleophilic vinylic substitution and unexpected products in the reaction of chlorotrifluoroethylene with [Re(CO)5]Na and [CpFe(CO)2]K

The mechanism of chloride substitution in CF₂CFCl with [Re(CO)₅]⁻ and [CpFe(CO)₂]⁻ anions is investigated experimentally and theoretically. The substitution reaction begins with the nucleophile addition to CF₂CFCl producing the carbenoid anion [MCF₂CFCl]⁻ (A) (M = Re(CO)₅, CpFe(CO)₂). This is shown by trapping the intermediate A with electrophiles - proton donor (t-BuOH) to give MCF₂CFClH or with CF₂CFRe(CO)₅ to give acylmetallate III, and by the formation of the substitution products CF₂CFM from the anion A, generated by the deprotonation of MCF₂CFClH with t-BuOK. 1,2-Shift of metal carbonyl group concerted with the α-elimination of chloride anion is proposed as the transformation pathway of carbenoid A into CF₂CFM. A competing process of carbene insertion into Fe-CO bond is proposed to explain the formation of (XI). The feasibility of these two pathways is confirmed by DFT (B3LYP/SDD and 6-31G^∗) calculations of the carbenes [MCF₂CF:] and carbenoid anions [MCF₂CFCl]⁻. Transition states (TS) for 1,2-shift (+3.2 kcal/mol) and for nucleophilic addition at CO ligand (+5.4 kcal/mol) are located for [(CO)₅ReCF₂CFCl]⁻, but only one TS corresponding to carbene insertion into Fe-CO bond (+2.1 kcal/mol) is located for [(CO)₂CpFeCF₂CFCl]⁻. The formation of other newly observed products, F(CO)CHFRe(CO)₅ (V) and Cp(CO)₂FeCCFeCp(CO)₂ (VIII) is also discussed.     

2-(2-甲基烯丙基)-3-(3-甲基-1,2-丁二烯基)环己-2-烯酮重排生成八元环化合物反应机理的理论研究

采用密度泛函理论B3LYP/6-31G(d,p)方法研究了2-(2-甲基丙烯基)-3-(3-甲基-1,2-丁二烯基)环己-2-烯酮重排生成八元环化合物在气相中的反应机理. 考虑了两条可能的反应途径: 途径1包含5个过程, 途径2包含两个过程. 从能量上看, 两条途径的决定速度步均是[1,5]氢迁移. 采用自洽反应场极化连续模型(PCM模型)和极化导体模型(CPCM模型)研究了反应体系在甲苯溶液中的溶剂效应. 结果表明, 气相和溶液中途径2均是较优途径, 并且甲苯对该反应的溶剂化效应不明显. 理论研究结果与实验观察结果一致, 并很好地解释了有关实验现象.