兔血浆中氟虫腈及其砜化物的高效液相色谱分析法

目的:建立兔血浆中氟虫腈(Fipronil)及其代谢物砜化物(Fipronil sulfone)的高效液相色谱检测法.方法:高效液相色谱仪为Agilent 1100系列;血浆经乙醚萃取浓缩,以Hypersil ODS-C18(4.6 mm×250 mm,5 μ m)为色谱分析柱;以乙腈-甲醇-水(26∶24∶50,V/V/V)为流动相,流速为1.0ml·min-1;检测波长为276 nm;内标为地西泮.对兔血浆中的氟虫腈及其砜化物进行检测.结果:氟虫腈及其砜化物浓度在0.05～5.00 mg·L-1范围内均具有良好的线性关系(r=0.999);最低检测限均为为0.05mg·L-1;相对回收率分别为(101.08±6.13)%和(100.68±4.78)%,绝对回收率分别为(80.24%±2.58)%和(81.77±2.64)%;日内精密度变异系数分别为(5.55±1.24)%和(5.59±1.25)%;日间精密度变异系数分别为(5.91±1.44)%和(7.27±1.20)%.结论:本研究采用的反相-高效液相色谱法快速、简便、灵敏、准确,可用于兔血浆氟虫腈及其砜化物的检测和毒物代谢动力学研究.     

A Low Temperature Polycondensation for the Preparation of Highly Fluorinated Poly(arylene ether sulfone)s Containing Crosslinkable Pentafluorostyrene Moieties

Summary: The polycondensation of pentafluorophenyl sulfone (PPSO) with hexafluorobisphenol A (6F‐BPA), or a model compound, 4‐phenoxylphenol (POPOH), has been studied in order to find optimized reaction conditions for the preparation of fluorinated poly(arylene ether sulfone)s (FPAESs). It was found that PPSO had a very high reactivity in N,N‐dimethylacetamide (DMAc), allowing the reaction to occur at temperatures as low as 22 °C, even in the absence of any catalyst. This reaction was promoted by the addition of a trace amount of potassium fluoride (KF). Increasing the amount of KF to 1.05 equiv enhanced the conversion and allowed the reaction to be completed in a short time. Under this reaction condition, KF acted as a catalyst to activate the phenol group and also acted as a base to absorb the HF, which was a by‐product of the polycondensation, to produce high molecular weight polymer. The use of calcium hydride (CaH₂) instead of KF as a base in this reaction produced a similar effect with a slightly lower reaction rate. Both base systems were also applicable to the reaction of pentafluorostyrene (FSt) with 6F‐BPA. However, a much higher reaction temperature (125 °C) was required due to the low reactivity of FSt. Reacting FSt with an excess of 6F‐BPA produced a mixture of mono‐ and di‐substituted products of FSt with a controllable ratio, which could further react with PPSO to produce a polymer containing crosslinkable FSt moieties both as end‐capping groups and inserting units. This structure allowed the molecular weight of the polymer and the content of FSt to be adjusted independently. Crosslinked films of this polymer demonstrated an excellent processability and performance in waveguide applications, having refractive indices of 1.5061 (TE) and 1.5038 (TM), and a straight waveguide loss of 0.7 dB · cm⁻¹.

Reaction scheme for the preparation of fluorinated poly(arylene ether sulfone)s.     

Enhanced activity of human N-myristoyltransferase by dimethyl sulfoxide and related solvents in the presence of serine/threonine-containing peptide substrates

Human N-myristoyltransferase (hNMT) activity was found to be stimulated several-fold by DMSO and its analogues in the presence of serine-containing peptide substrates. DMSO caused a concentration-dependent 10-fold stimulation of hNMT activity in the presence of a pp60(src)-derived peptide substrate (Gly-Ser-Ser-Lys-Ser-Lys-Pro-Lys-Arg). However, the stimulation of hNMT activity was not observed by DMSO when a cyclic AMP (cAMP)-dependent protein kinase-derived Ser-free peptide substrate (Gly-Asn-Ala-Ala-Ala-Ala-Lys-Lys-Arg-Arg) was used. These findings suggested that the effect of DMSO is on the substrate rather than on the enzyme. When a MARCKS (myristoylated alanine-rich C-kinase substrate)-derived peptide substrate (Gly-Ala-Gln-Phe-Ser-Lys-Thr-Ala-Arg-Arg) and the M2 gene segment of the reovirus type 3 peptide substrate (Gly-Asn-Ala-Ser-Ser-Ile-Lys-Lys-Lys) were used, hNMT activity was increased by approximately 8.5- and 7-fold, respectively. Dimethyl sulfone (20%) increased hNMT activity between 2.5- and 3.5-fold in the presence of pp60(src), MARCKS, and M2 gene segment peptides. Dimethyl formamide (20%) increased the hNMT activity by 8.5-, 8.5-, 5.5- and 3.5-fold when pp60(src), MARCKS, M2, and cAMP-dependent protein kinase-derived peptide substrates were used, respectively. Acetone (20%) also increased the hNMT activity by 20-fold in the presence of the pp60(src) peptide substrate. Dimethyl ammonium chloride (20%) caused about 6.5- and 2.5-fold increases in the hNMT activity in the presence of the pp60(src) and cAMP-dependent protein kinase-derived peptide substrates, respectively. Infrared spectroscopy showed a decreased intensity in the band at 3500-3600cm(-1) when the infrared spectrum of the pp60(src)-derived peptide was determined in the presence of DMSO. These results suggest the involvement of hydrogen bonding between the heteroatoms of the organic molecules and the hydrogen atoms of the free hydroxyl groups of the serine/threonine-containing peptide substrates. Such interactions appear to enhance the activity of hNMT towards its serine-containing substrates.     

Effect of Sulfonation Level on Sulfonated Aromatic Poly(ether sulfone) Membranes as Polymer Electrolyte for High‐Temperature Polymer Electrolyte Membrane Fuel Cells

Sulfonated poly(ether sulfone)s (SPESs) are developed which have different sulfonation level as a polymer electrolyte membrane for high‐temperature operation. The sulfonation level of SPESs is calculated by ¹H NMR, and the molecular structure and crystalline structure of SPESs are evaluated by Fourier transform infrared and X‐ray diffraction. SPES membranes are thermally stable up to 250 °C. SPES membranes can keep their shapes at 120 °C and 23%RH. Water uptake at 120 °C and 23%RH is 5.7–6.4 wt%, while Nafion 212 shows 2.4 wt%. Proton conductivity measurements of SPESs are carried out from 30 to 120 °C at different relative humidity. With increasing sulfonation level of SPES, proton conductivity increases in all humidity. The proton conductivity obtained from all SPESs is more than 100 mS cm^–1 at 120 °C in high humidity (>90%RH), and high‐sulfonation SPES shows higher conductivities than Nafion 212 at 120 °C, 20%RH.

     

Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain

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二维波浪形构型锌配合物的合成、表征及性质研究

目的:研究二维波浪形构型锌配合物的结构与荧光性质之间的关系,探究新型荧光材料的合成方法。方法:溶剂热条件下,硝酸锌与4,4'-二(苯并咪唑-1-甲基)联苯和4,4'-二羧基二苯基砜的自组装生成一个新型配合物[Zn(C14H18SO6)(C28H22N4)]n,并对配合物进行X-射线单晶衍射、热重分析、X-射线粉末衍射及固体荧光表征。结果:该配合物具有波浪形二维层状结构,且结构中苯并咪唑环之间存在强的π-π作用,使得该配合物在379 nm(激发波长为298 nm)处表现出优于配体的强荧光光谱。结论:合成了一种具有荧光性质的新型配合物,研究了配合物结构与性质之间的关系,为新型荧光配合物的设计合成提供参考。     

Toxicology and carcinogenesis studies of p,p'-dichlorodiphenyl sulfone in rats and mice.

p,p'-Dichlorodiphenyl sulfone (DDS) is used as a starting material in the production of polysulfones and polyethersufones, a family of thermoplastics. DDS was studied because of its high production volume and use. In toxicology studies, 10 Fischer 344 rats and 10 B6C3F1 mice/sex/group were fed diets containing 0, 30, 100, 300, 1,000 or 3,000 ppm DDS for 14 weeks. All animals survived until the end of the studies. Mean body weights of groups exposed to 300 ppm or greater were significantly decreased. Liver and kidney in rats and liver in mice were the major target organs of DDS toxicity. Dose-related increases in liver weights and incidences of centrilobular hepatocyte hypertrophy were observed in DDS-exposed groups. Nephropathy was seen in male and female rats only at and above 300 ppm. Neurotoxicity evaluations were negative in DDS-treated animals. Clinical chemistry and hematology parameters were minimally affected. In the 2-year toxicity and carcinogenicity studies, 50 rats and 50 mice/sex/group were fed diets containing 0, 10 (male rats), 30, 100, or 300 ppm DDS for 104 to 105 weeks. Survival of exposed groups was not affected. There were no clinical signs of toxicity related to DDS exposure. Final mean body weights were 2-17% lower in DDS-treated groups. Liver was the only target organ of DDS-induced toxicity. The incidence of centrilobular hepatocyte hypertrophy in mice and rats, and the incidence of bile duct hyperplasia and centrilobular degeneration in female rats was significantly greater than in controls. A no-observed-adverse-effect level (NOAEL) of 30 ppm DDS in the diet (1.5 mg/kg body weight) was established for rats. DDS was not carcinogenic in these studies.     

Pharmacokinetic properties of lansoprazole (30-mg enteric-coated capsules) and its metabolites: A single-dose, open-label study in healthy Chinese male subjects

Background: Lansoprazole, a benzimidazole derivative, is indicated for the treatment of various peptic diseases. It is metabolized mainly in the liver, and its primary active metabolites present in plasma are 5′-hydroxy lansoprazole and lansoprazole sulfone. Few data are available on the pharmacokinetic properties of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone, which can be used to measure cytochrome P450 (CYP) 2C19 activity.Objectives: The aims of this study were to investigate the clinical plasma pharmacokinetic properties of lansoprazole and its metabolites in healthy Chinese male volunteers, and to assess the influences of CYP2C19 on the pharmacokinetics of lansoprazole.Methods: Healthy adult Chinese male volunteers were enrolled in this single-dose, open-label study. All patients received a single oral enteric capsule containing 30 mg of lansoprazole after a 12-hour overnight fast. Serial blood samples were collected immediately before (0 hour) and at 20, 40, 60, 90, 120, and 150 minutes and 3, 4, 6, 8, 10, 12, 15, and 24 hours after study drug administration. The plasma concentrations of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone were determined using a validated internal standard high-performance liquid chromatography—tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic properties (including C_max, T_max, elimination t_½ [t_½z], mean residence time [MRT], AUC_0-24, AUC_0−∞, apparent oral clearance [CL_z/F], and apparent volume of distribution [V_z/F]) were determined using the noncompartmental method.Results: Twenty volunteers (mean [SD] age, 34.9 [2.9] years; weight, 64.6 [2.2] kg; height, 171.3 [3.3] cm) were enrolled in and completed the study. The mean (SD) pharmacokinetic properties of lansoprazole were as follows: C_max, 1047 (344) ng/mL; T_max, 2.0 (0.7) hours; t_½z, 2.24 (1.43) hours; MRT, 3.62 (0.87) hours; AUC₀₋₂₄, 3388 (1484) ng/mL/h; AUC_0-∞, 3496 (1693) ng/mL/h; CL_z/F, 9.96 (3.74) L/h; and V_z/F, 32.83 (11.74) L. The findings with 5′-hydroxy lansoprazole and lansoprazole sulfone, respectively, were as follows: C_max, 111.2 (41.8) and 66.6 (52.9) ng/mL; T_max, 2.1 (0.8) and 1.9 (0.8) hours; t_½z, 2.31 (1.18) and 2.52 (1.54) hours; and AUC₀₋₂₄, 317.0 (81.2) and 231.9 (241.7) ng/mL/h. No adverse events were reported throughout the study.Conclusions: In these healthy Chinese male volunteers administered a single oral dose of lansoprazole 30 mg, absorption of lansoprazole was rapid (mean C_max, 1047 ng/mL; T_max, ~2.0 hours). Its 2 primary active metabolites, 5′-hydroxy lansoprazole and lansoprazole sulfone, were identified in measurable quantities in plasma (C_max, 111.2 and 66.6 ng/mL, respectively; and T_max, 2.1 and 1.9 hours). The plasma t_½z did not appear to reflect the duration of suppression of gastric acid secretion: the t_½z values of lansoprazole and the 2 metabolites were ~2 to 2.5 hours, while the acid-inhibitory effect lasted >24 hours. C_max, AUC, and t_½z of lansoprazole, and especially lansoprazole sulfone, varied. Differences in metabolism types and/or genotype of CYP2C19 should be taken into account when planning a lansoprazole dosing regimen.     

In vivo pharmacokinetic study and oral glucose tolerance test of sulfoxide analogs of GPR40 agonist TAK-875

TAK-875 (compound 1 ) was the only GPR40 agonist with promising oral glucose-lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK-875 sulfoxide analog 2 , which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R, S, 100.0% de). In vitro biological evaluation revealed that the sulfoxide analogs 3 and 4 possessed comparable GPR40 agonist activity to TAK-875. Herein, in order to further evaluate the druglikeness of TAK-875 sulfoxide analogs, the pharmacokinetic properties of compounds 2 , 3 , and 4 in rats were investigated and compared with that of TAK-875. The results showed that sulfoxide ( 2 , 3 , and 4 ) and sulfone (TAK-875) could be converted into each other in different degrees in vivo. Interestingly, compound 3 showed higher drug exposure calculated by the AUC sum of sulfoxide and sulfone in plasma than TAK-875, 2 and 4 . In order to further investigate the in vivo glucose-lowering potency of sulfoxide analogs, asymmetric synthesis was carried out and led to two sulfoxides with moderate de values, 5 (S, S, 66.4% de) and 6 (R, S, 71.0% de). The following oral glucose tolerance test (OGTT) in rats showed that 5 (S, S, 66.4% de) had stronger glucose-lowering effect in vivo than 6 (R, S, 71.0% de) and TAK-875, which could be partly rationalized by the superior pharmacokinetic property of sulfoxide 3 (the main component of 5 ) relative to sulfoxide 4 (the main component of 6 ) and TAK-875.     

Development of molecular driven screening for desulfurizing microorganisms targeting the dszB desulfinase gene

COnsensus DEgenerate Hybrid Oligonucleotide Primers (CODEHOP) were developed for the detection of the dszB desulfinase gene (2′-hydroxybiphenyl-2-sulfinate desulfinase; EC 3.13.1.3) by polymerase chain reaction (PCR), which allow to reveal larger diversity than traditional primers. The new developed primers were used as molecular monitoring tool to drive a procedure for the isolation of desulfurizing microorganisms. The primers revealed a large dszB gene diversity in environmental samples, particularly in diesel-contaminated soil that served as inoculum for enrichment cultures. The isolation procedure using the dibenzothiophene sulfone (DBTO₂) as sole sulfur source reduced drastically the dszB gene diversity. A dszB gene closely related to that carried by Gordonia species was selected. The desulfurization activity was confirmed by the production of desulfurized 2-hydroxybiphenyl (2-HBP). Metagenomic 16S rRNA gene sequencing showed that the Gordonia genus was represented at low abundance in the initial bacterial community. Such observation highlighted that the culture medium and conditions represent the bottleneck for isolating novel desulfurizing microorganisms. The new developed primers constitute useful tool for the development of appropriate cultural-dependent procedures, including medium and culture conditions, to access novel desulfurizing microorganisms useful for the petroleum industry.