High quality drug screening by capillary electrophoresis: A review

High quality assays are needed in drug discovery to reduce the high attrition rate of lead compounds during primary screening. Capillary electrophoresis (CE) represents a versatile micro-separation technique for resolution of enzyme-catalyzed reactions, including substrate(s), product(s), cofactor(s) and their stereoisomers, which is needed for reliable characterization of biomolecular interactions in free solution. This review article provides a critical overview of new advances in CE for drug screening over the past five years involving biologically relevant enzymes of therapeutic interest, including transferases, hydrolases, oxidoreductases, and isomerases. The basic principles and major configurations in CE, as well as data processing methods needed for rigorous characterization of enzyme inhibition are described. New developments in functional screening of small molecules that modulate the activity of disease-related enzymes are also discussed. Although inhibition is a widely measured response in most enzyme assays, other important outcomes of ligand interactions on protein structure/function that impact the therapeutic potential of a drug will also be highlighted, such as enzyme stabilization, activation and/or catalytic uncoupling. CE offers a selective platform for drug screening that reduces false-positives while also enabling the analysis of low amounts of complex sample mixtures with minimal sample handling.     

New Synthetic Approaches to Substituted Pyridine-2-(1H)-ones Clubbed with Substituted Aryl Diazo Substituents

6-Triazolylpyridone derivatives were synthesized by coupling 4-(4-methoxyphenyl)-6-(1H-1,2,4-triazol-1-yl)-1-(3-chlorophenyl)pyridin-2(1H)-one with substituted benzenediazonium chlorides in the form of two isomers, which were separated by column chromatography and characterized by ¹H and ¹³C NMR. Following the green approach, solvents were avoided as much as possible. The reaction monitoring was carried out by gas chromatography as well as thin-layer chromatography. The scope and limitation of the method are discussed. The structures of all the compounds have been assigned unambiguously on the basis of elemental analysis, infrared, and NMR spectral data and have been evaluated for antimicrobial and antitubercular activities.     

An Efficient and Highly Stereoselective Synthesis of β,γ-Trans-β-Benzoyl-γ-Aryl-γ-Butyrolactones

Benzoylmethyltriphenylarsonium bromide 6 in the presence of potassium carbonate reacted with 2,2-dialkyl-1,3-dioxa-5-substituted-benzylidene-4,6-dione 2 at room temperature to give β,γ-trans-β-benzoyl-γ-aryl-γ-butyrolactones 7 in good yield.     

Nano-TiO2: An Efficient and Reusable Heterogeneous Catalyst for Ring Opening of Epoxides Under Solvent-Free Conditions

Nano-TiO₂ is an effective heterogeneous catalyst for the ring opening of epoxides with aromatic amines to afford β-amino alcohols in good to excellent yields at room temperature under solvent-free conditions. It was found that the catalyst is recyclable, and the activity of the catalyst was not weakened markedly even after several reaction cycles. In addition, the catalytic activity of TiO₂ strongly depends on particle size or surface area.     

Zearalenone Mimics: Synthesis of (E)-6-(1-Alkenyl)-substituted β-Resorcylic Acid Esters

Two versatile strategies for the synthesis of mimics of the Fusarium mycotoxin zearalenone (1) have been developed. Optimized preparation of (E)-6-(1-alkenyl) substituted β-resorcylic acid esters was realized via ortho-directed lithiation of variable substrates combined with allylation/isomerization or via formylation/Schlosser–Wittig olefination using different protective group patterns. Spontaneous decarboxylation of (E)-6-(1-alkenyl) substituted β-resorcylic acids indicated the influence of this substituent on the chemical behavior of these compounds. These mimics were already used for the development of optimized standard protocols for the synthesis of phase II metabolites of ZEN (glucosides, glucuronides), and further applications (i.e., sulfate conjugates) are still under investigation.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Isolation and Crystal Structure of 4β,6α,9α- Trimethy-2-carboxyltricyclo[6.3.0.0^（4,5）]undec-2-ene

The title compound, 4β,6α,9α-trimethy-2-carboxyltricyclo[6.3.0.0^（4,5）]undec-2-ene, is a sesquiterpene which was first isolated from Ligularia caloxantha and characterized by MS and NMR. In addition, the structure was determined by X-ray single-crystal diffraction. It crystallizes in orthorhombie, space group P212121 with a = 8.197（2）, b = 14.876（3）, c = 22.281（6） A, α = β = γ = 90°, V = 2716.9（11） ]A^3, Z = 8, C15H22O2, Mr = 234.34, Dc = 1.146 g/cm^3, μ（MoKa） = 0.074 mm^-1, F（000） = 1024, the final R = 0.0384 and wR = 0.0856 for 6200 independent reflections （Rint = 0.066） and 2538 observed ones （I 〉 2σ（I））. In the molecule, there are three fused five-membered rings; while in this crystal form, the asymmetric unit contains two molecules of the same hand and they are linked together by two intermolecular O-H...O hydrogen bonds to form a dimer.     

Phase transition between two anhydrous modifications of NaHSO4 mediated by heat and water

The phase transition between the two anhydrous modifications of NaHSO₄ (α and β) was studied using Raman spectroscopy and differential scanning calorimetry. These measurements indicate that β-NaHSO₄ is a metastable phase and readily undergoes phase transition to thermodynamically stable α-NaHSO₄ with an exothermic enthalpy change of 3.5 kJ/mol. Both thermal (temperatures >434 K) and chemical (exposure to H₂O) pathways were identified for this transition. The transition is irreversible, and α-NaHSO₄ is an intermediate phase between β-NaHSO₄ and NaHSO₄·H₂O. The possible mechanism of the phase transition is discussed.     

抗癌药β-榄香烯分子内部运动的13C核自旋弛豫研究

首次应用变温实验方法和¹³C核自旋弛豫方法研究了抗癌药β-榄香烯小分子的内部运动状况。结果表明β-榄香烯分子的六元环在所研究的温度范围(298~318K)内几乎是刚性的。该分子的整体滚动自扩散活化能为14kJ/mol.其六元环外侧链基团CH₂=CCH₃-和CH₂=CH-的整体内旋转扩散活化能均为19kJ/mol.而与该六元环直接相连的甲基的内旋转扩散活化能为18kJ/mol.这个数值大大高于连在六元环上不同位置的两个侧链基团CH₂=CCH₃一中甲基的内旋转扩散活化能(其数值分别为了7kJ/mol和2.8KJ/mol).3个不同位置的甲基的内旋转扩散活化能有很大差别可能是由它们所处的分子空间环境不同而引起的。     

关于(α,β) -度量的S -曲率

给出(α,β) -度量F=α\phi(β/α)的S -曲率的计算公式. 证得对一般的(α,β) -度量,当β为关于α长度恒定的Killing1 -形式时,S=0.研究了Matsumoto -度量F=α²/(α-β)和(α,α) -度量F=α+εβ+kβ²/α)的S -曲率, 证得S=0当且仅当β为关于α长度恒定的Killing1 -形式.同时还得到这两类度量成为弱Berwald度量的充要条件.其中\phi(s)为光滑函数,α(y)=\sqrt{a_ij(x)yⁱy^j}为黎曼度量,β(y)=b_i(x)yⁱ为非零1 -形式且ε,k≠ 0为常数.     

Microwave-assisted immobilization of β-cyclodextrin on PEGylated Merrifield resins

β-Cyclodextrin was immobilized on PEGylated Merrifield resin through cross-linking with 1,6-hexamethylene diisocyanate (HMDI) reagent, using conventional and microwave-assisted methodologies. FT-IR analysis of the solid intermediates indicated the attachment of the linker arm to the resin due the appearance of characteristic bands centered at 1716 and 2270 cm⁻¹ and the attachment of cyclodextrin to the resin was accompanied with increased absorption at the OH stretching regions (3330-3400 cm⁻¹). β-Cyclodextrin linked PEGylated resins are water insoluble and can be used to trap volatile organic compounds (VOCs) from water and subsequently be analyzed by headspace HS/GC, after simple filtration and drying steps.