Addressing the metabolic activation potential of new leads in drug discovery: a case study using ion trap mass spectrometry and tritium labeling techniques

Metabolic activation of drug candidates to electrophilic reactive metabolites that can covalently modify cellular macromolecules may result in acute and/or idiosyncratic immune system-mediated toxicities in humans. This presents a significant potential liability for the future development of these compounds as safe therapeutic agents. We present here an example of an approach where sites of metabolic activation within a new drug candidate series were rapidly identified using online liquid chromatography/multi-stage mass spectrometry on an ion trap mass spectrometer. This was accomplished by trapping the reactive intermediates formed upon incubation of compounds with rat and human liver microsomes as their corresponding glutathione conjugates and mass spectral characterization of these thiol adducts. Based on the structures of the GSH adducts identified, potential sites and mechanisms of bioactivation within the chemical structure were proposed. These metabolism studies were interfaced with iterative structural modifications of the chemical series in order to block these bioactivation sites within the molecule. This strategy led to a significant reduction in the propensity of the compounds to undergo metabolic activation as evidenced by reductions in the irreversible binding of radioactivity to liver microsomal material upon incubation of tritium-labeled compounds with this in vitro system. With the efficiency and throughput achievable with such an approach, it appears feasible to identify and address the metabolic activation potential of new drug leads during routine metabolite identification studies in an early drug discovery setting.     

双波长K系数—标准加入吸光光度法同时测定锰和锌

研究应用双波长K系数—标准加入吸光光度法同时测定锰和锌二组分混合物.试验确定了锰和锌测定中K_(Mn)与K_(Zn)的回归方程.对合成试样、人发试样测定,结果满意.     

脱蜡剂DF-1的气相色谱-傅里叶变换红外光谱联用分析

脱蜡剂ＤＦ－１是一种含多种有机成分的碳氢化合物，经气相色谱－红外光谱联用分析后，确定了这些组分的组成与含量。     

聚二甲基硅氧烷基质微流控芯片通道的氧气氛改性研究

通过将新制的PDMS微流控芯片置于氧气氛中对通道表面进行处理的简单方法,使电渗流大小及稳定性有了显著的改善。同时研究了氧气处理PDMS通道表面的时间对电渗流的影响,得到氧气处理的最佳时间为3d。讨论了氧气作用于PDMS芯片表面的机理。在氧气处理3d的PDMS微流控芯片上进行氨基酸分离实验,得到较好的分离效果。     

刺楸中新七糖皂苷的结构解析

从刺楸Kalopanax septemlobus(Thunb．)Koidz．树皮乙醇提取物中分离得到一种七糖三萜皂苷(1),其分子结构经化学方法和波谱分析(IR,ESI-MS,^1H NMR,^13C NMR,^1H-^1H COSY,^1H-^1H TOCSY,HMQC,HMBC)鉴定为3-O-β-D-吡喃木糖(1→4)-β-D-吡喃木糖(1→3)-α-L-吡喃鼠李糖(1→2)-α-L-吡喃阿拉伯糖常春藤皂苷配基28-O-α-L-吡喃鼠李糖(1→4)-β-D-吡喃葡萄糖(1→6)-β-D-吡喃葡萄糖酯苷,命名为刺皂苷Ⅰ(septemlosideⅠ)。     

HMS和NaY固载酒石酸钛配合物的研究

利用化学键合和“瓶中造船”方法,成功地将酒石酸钛配合物接枝到HMS(heragonal mesoporous silicas)上或包络合于微孔NaY内.FT-IR表征表明酒石酸钛在HMS上是通过与载体表面羟基发生交换作用而被固载的;在NaY载体上则是通过包络合被封装在载体的超笼内.UV-Vis可见漫反射表征表明两类固载型催化剂有着相似的钛配位环境.在催化肉桂醇环氧化反应中,HMS键合型催化剂的反应转化率比NaY包络型催化剂的高;但后者在环氧化选择性上要高于前者.回收样品的重复使用实验结果表明,两类固载型催化剂在重复使用过程中均存在不同程度的失活.     

Performances of Lactobacillus brevis for Producing Lactic Acid from Hydrolysate of Lignocellulosics

Utilizing all forms of sugars derived from lignocellulosic biomass via various pretreatment and hydrolysis process is a primary criterion for selecting a microorganism to produce biofuels and biochemicals. A broad carbon spectra and potential inhibitors such as furan, phenol compounds and weak acids are two major obstacles that limited the application of dilute-acid hydrolysate of lignocellulosics in lactic acid fermentation. Two strains of bacteria isolated from sour cabbage, S3F4 (Lactobacillus brevis) and XS1T3-4 (Lactobacillus plantrum), exhibited the ability to utilize various sugars present in dilute-acid hydrolysate of biomass. The S3F4 strain also showed strong resistance to potential fermentation inhibitors such as ferulic acid and furfural. Fermentation in flasks by this strain resulted in 39.1 g/l of lactic acid from dilute acid hydrolysates of corncobs that had initial total sugar concentration of 56.9 g/l (xylose, 46.4 g/l; glucose, 4.0 g/l; arabinose, 6.5 g/l). The hydrolysate of corncobs was readily utilized by S3F4 without detoxification, and the lactic acid concentration obtained in this study was higher compared to other reports.     

Simultaneous Determination of Lathyrane Diterpenoids by NPLC-DAD in the Seeds of Euphorbia lathyris and “ZI-JIN-DING” Pastille

A novel, simple and specific normal-phase liquid chromatography (NPLC) method has been developed for simultaneous determination of the four lathyrane diterpenoids, lathyrol-5,15-diacetate-3-benzoate (1, L₃), lathyrol-5,15-diacetate-3,7-dibenzoate (2, L₂), Δ6,17-epoxide-5,15-diacetate-3-phenylacetate (3, L₁), lathyrol-5,15-diacetate-3-nicotinate (4, L₈) in the hexane extract of the seeds of Euphorbia lathyris and “ZI-JIN-DING” pastille. The method showed good linearity for the four analytes (r ² > 0.99), the intra-day and inter-day variations (RSD) were less than 3%, and the recoveries ranged from 99.4 to 100.6%. This method was successfully used to determine the four lathyrane diterpenoids in the seeds of Euphorbia lathyris and “ZI-JIN-DING” pastille, and could be applied for their quality control.     

Effect of acetic acid on CO2 corrosion of carbon steel in NaCl solution

Potentiodynamic sweep and electrochemical impedance spectroscopy measurements were applied to investigate the effects of both temperature and acetic acid (HAc) on the anodic and cathodic reactions in CO₂ corrosion of P110 steel in 3.5% NaCl solution. The temperatures were controlled at 30 and 60 °C. The concentrations of HAc were controlled at 0, 1000, 3000 and 5000 ppm. In this work, the corrosion parameters of polarization curves, such as corrosion potential (E_corr), corrosion current density (i_corr), and anodic and cathodic branch slopes (b_a and b_c), are presented and discussed in detail. In addition, the equivalent circuit models and ZsimpWin software were utilized to discuss the Nyquist plots. The plots showed that the E_corr values shifted in the positive direction as the HAc concentration increased. The i_corr values increased with the increase in HAc concentration, indicating that HAc could accelerate the corrosion. The impedance spectra measured at 30 and 60 °C have different time constants and characterization. The coverage fraction θ and the thickness L of corrosion film are two most important controlled variables that influence and control the CO₂ corrosion mechanisms. Copyright © 2010 John Wiley & Sons, Ltd.