Conformational analysis of some antibacterial agent 4-aminodiphenyl sulfones

Conformational free energy calculations using an empirical potential function (ECEPP/2) and hydration shell model were carried out on the four 4-aminodiphenyl sulfone analogues of 4, 4′-diamino-2′-methyldiphenyl sulfone, 4, 2′, 4′-triaminodiphenyl sulfone, 4, 4′-diaminodiphenyl sulfone, and 4-aminodiphenyl sulfone as antibacterial agents onMycobacterium lufu. The conformational energy was minimized from starting conformations which included possible combinations of torsion angles in the molecule. The conformational entropy change of each conformation was computed using a harmonic approximation. To understand the hydration effect on the conformation of the molecule in aqueous solution, the contributions of water-accessible volume and the hydration free energy of each group or atom in the lowest-free-energy conformation was calculated and compared each other. From comparison of the computed lowest-free-energy conformations of four analogues with their antibacterial activities, it is known that the conformation and the hydrophobicity of sulfonyl group and its adjacent carbon atom in each compound are the essential factors to show the strong antibacterial activity.     

Synthesis,Antibacterial Activities,and 3D‐QSAR of Sulfone Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

A series of sulfone derivatives containing 1, 3, 4‐oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC₅₀ values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b , and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC₅₀ values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC₅₀ values of 45.91 and 216.70 μg/mL, respectively. The structure–activity relationship (SAR) of compounds was studied using three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D‐QSAR models effectively predicted the correlation between inhibitory activity and steric–electrostatic properties of compounds.     

聚焦超声联合不同药物治疗慢性宫颈炎的疗效对比分析

目的探讨聚焦超声联合聚甲酚磺醛溶液治疗慢性宫颈炎与聚焦超声加西瓜霜喷剂治疗慢性宫颈炎的疗效对比分析。方法390例确诊的中、重度宫颈糜烂患者根据就诊先后顺序随机分为治疗组A（聚焦超声联合聚甲酚磺醛溶液治疗）、治疗组B（聚焦超声联合西瓜霜喷剂治疗）和对照组（聚焦超声治疗）各130例,对3组的疗效进行对比分析。结果治疗2个月后,对照组总有效率为79．23％,治疗组A总有效率为90．00％。治疗组B总有效率为81．54％。3组总有效率比较差异有统计学意义（P〈0．05）。治疗3个月后,对照组总率为85．38％,治疗组A总有效率98．46％,治疗组B总有效率为86．92％,3组总有效率比较差异有统计学意义（P〈0．05）。且治疗3个月后3组的总有效率均较治疗2个月后的疗效明显增加。结论聚焦超声联合聚甲酚磺醛溶液或联合西瓜霜喷剂治疗慢性宫颈炎疗效均优于单纯聚焦超声治疗,且聚焦超声联合聚甲酚磺醛溶液治疗慢性宫颈炎疗效显著,能明显改善患者的症状,值得临床推广。     

Dimethyl sulfone in human cerebrospinal fluid and blood plasma confirmed by one-dimensional (1)H and two-dimensional (1)H-(13)C NMR

(1)H-NMR spectroscopy at 500 MHz was used to confirm that a previously unidentified singlet resonance at 3.14 ppm in the spectra of cerebrospinal fluid and plasma samples corresponds to dimethyl sulfone (DMSO(2)). A triple resonance inverse cryogenic NMR probe, with pre-amplifier and the RF-coils cooled to low temperature, was used to obtain an (1)H-(13)C HSQC spectrum of CSF containing 8 microM (753 ng/ml) DMSO(2). The (1)H-(13)C correlation signal for DMSO(2) was assigned by comparison with the spectrum from an authentic reference sample. In plasma and CSF from healthy controls, the concentration of DMSO(2) ranged between 0 and 25 micromol/l. The concentration of DMSO(2) in plasma from three of four patients with severe methionine adenosyltransferase I/III (MAT I/III) deficiency was about twice the maximum observed for controls. Thus, DMSO(2) occurs as a regular metabolite at low micromolar concentrations in cerebrospinal fluid and plasma. It derives from dietary sources, from intestinal bacterial metabolism and from human endogenous methanethiol metabolism.     

Antigen delivery to dendritic cells by poly(propylene sulfide) nanoparticles with disulfide conjugated peptides: Cross-presentation and T cell activation

Vaccines aiming to activate cytotoxic T cells require cross-presentation of exogenous antigen by antigen-presenting cells (APCs). We recently developed a synthetic nanoparticle vaccine platform that targets lymph node-resident dendritic cells (DCs), capable of mounting an immune response to conjugated antigen. Here, we explore routes of processing and the efficiency of MHC I cross-presentation of OVA peptides conjugated using both reducible and non-reducible linkages, exploring the hypothesis that reduction-sensitive conjugation will lead to better antigen cross-presentation. Both clathrin and macropinocytic pathways were implicated in nanoparticle uptake by colocalization and inhibitor studies. Cross-presentation by DCs was demonstrated by direct antibody staining and in vitro stimulation of CD8(+) T cells from OT-I mice and was indeed most efficient with the reduction-sensitive conjugation. Similarly, we observed IFN-γ production by CD4(+) T cells from OT-II mice. Finally, immunization with the OVA peptide-bearing nanoparticles resulted in in vivo proliferation and IFN-γ production by adoptively transferred CD8(+) OT-I T cells and was also most efficient with reduction-sensitive linking of the peptide antigen. These results demonstrate the relevance of the poly(propylene sulfide) nanoparticle vaccine platform and antigen conjugation scheme for activating both cytotoxic and helper T cell responses.     

Understanding Loss of Soluble High Molecular Weight Species during Filtration of Low Concentration Therapeutic Monoclonal Antibodies

Sterile filtration is an integral step in the manufacturing process of biological therapeutics. Protein adsorption to the surface of the filter is an unfortunate, common occurrence that can result in manufacturing difficulties, such as filter fouling or product loss. Although many filters have surface modifications to minimize adsorption, under certain conditions binding can still occur. We observed the loss of high molecular weight species (HMWS) during sterile filtration of eight different therapeutic monoclonal antibodies formulated at low protein concentrations across a commonly used hydrophilic polyvinylidene fluoride or polyvinylidene difluoride (PVDF) filter membrane. The protein absorption was specific to HMWS, and each antibody exhibited different degrees of filter adsorption. Debye screening length parameters of the solution (e.g. ionic strength) were adjusted, and influenced the amount of HMWS lost during filtration. Additionally, HMWS of a representative antibody (mAb1) were observed to be more positively charged than other size variants by ion-exchange chromatography. From these results, it is concluded that this HMWS loss is due to electrostatic interactions between HMWS and the filter surface. This adsorption can be reduced by increasing the ionic strength of the buffer matrix, demonstrating the influence of the Debye screening length in the filtration of low concentration proteins.     

Multipolar mitotic cells in the human cell line NHIK 3025 following treatment with the mitotic inhibitor NY 4137

Summary Treatment of human NHIK 3025 cells during interphase with the mitotic inhibitor 2-(2-thenyl) sulfonyl-5-bromopyrimidine (NY 4137) induced the formation of multipolar mitotic cells. A 4 h pulse treatment with 0.010 mM NY 4137 induced the formation of such cells regardless of whether treatment occurred in G1 or S phase. Approximately 35% of the cells originating from such multipolar mitotic divisions had less-than-normal G1 DNA content. Recordings of the DNA content of these small cells by means of flow cytometry showed that the amount of DNA per cell varied randomly. Subpopulations were separated by centrifugal elutriation on the basis of differences in cellular volume. Simultaneous two-parametric recordings of DNA versus total cellular protein showed that even though cells contained an amount of DNA less than G1 cells, there was a proportionality between DNA content and protein content despite variations in cell size.Fellow of the Norwegian Cancer SocietyThe author's name was previously: Mina E. Holm Nygaard     

二乙烯基砜交联的可德胶化学水凝胶的制备与表征

以二乙烯基砜（DVS）作为交联剂通过亲电加成反应制备了可德胶化学水凝胶。采用傅里叶变换红外光谱（FT-IR）、扫描电子显微镜（SEM）和质构分析手段表征了所得凝胶的结构与性能,并对其形貌、溶胀率以及水凝胶的力学性质与制备条件的关系进行了研究。结果表明：所得凝胶网络结构较为致密均匀,溶胀率依赖于交联度。可德胶化学水凝胶的强度和韧性可以通过DVS的用量、可德胶的浓度和碱溶液的浓度进行调控。     

Unusual base‐catalyzed exchange in the synthesis of deuterated PF‐2413873a

The preparation of deuterated PF‐2413873 (4‐[3‐cyclopropyl‐1‐(methanesulfonylmethyl)‐5‐methyl‐1H‐pyrazol‐4‐yl]oxy‐2,6‐dimethylbenzonitrile, 1) is described for use as a bioanalytical standard in clinical trials. Two strategies were investigated. The sulfone‐containing substituent was labelled by base‐catalyzed exchange, but unacceptable deuterium loss was noted under assay conditions. Alternatively, labelling 4‐cyano‐3,5‐dimethylphenol was achieved by heating with deuterium oxide over platinum oxide. After building up the pyrazole ring we discovered that, during the subsequent alkylation to attach the methylthiomethyl group, the base, potassium t‐butoxide, caused unwanted scrambling of deuteriums on the aromatic portion and the methylthiomethyl group. Thus, it was necessary to remove all base‐labile hydrogens to prevent their exchange. This was accomplished by alkylating the pyrazole with per‐deuterated chloromethyl methylsulfide, oxidation to the sulfone, and selective removal of its deuteriums by treatment with sodium hydroxide. The unusual sensitivity and selectivity of these base‐promoted exchange reactions are discussed. Thus, 4‐[3‐cyclopropyl‐1‐(methanesulfonylmethyl)‐5‐methyl‐1H‐pyrazol‐4‐yl]oxy‐[²H₆]2,6‐dimethyl‐[3,5‐²H]benzonitrile (17) was obtained, labelled with eight deuterium atoms and an acceptable D₀/D₈ ratio. Copyright © 2009 John Wiley & Sons, Ltd.     

Distribution of fipronil in humans,and adverse health outcomes of in utero fipronil sulfone exposure in newborns

Fipronil is a highly effective insecticide with extensive usages; however, its distribution and toxic/health effects in the human population after chronic exposure have not yet been clearly identified. Our objectives were to determine the levels of serum fipronil and fipronil sulfone, a primary fipronil metabolite, in a general and sensitive human population using a birth cohort of parent-infant triads in Korea. We further investigated whether in utero exposure to fipronil and fipronil sulfone can affect health outcomes in newborn infants.Blood and umbilical cord blood from 169 participants, 59 mother-neonate pairs and 51 matching biological fathers, were collected; serum fipronil and fipronil sulfone (both blood and cord blood) and serum thyroid hormones (cord blood) were measured. Demographic, physiological, behavioral, clinical, and socioeconomic data for each participant were collected via a one-on-one interview and a questionnaire survey.Fipronil sulfone was detected in the serum of mothers, fathers, and infantile cord blood, while fipronil itself was not. Maternal fipronil sulfone levels were correlated to those of matched biological fathers and newborn infants. Adjusted analyses identified significant associations between parental fipronil sulfone levels and household income. Infantile fipronil sulfone levels were significantly associated with both maternal and paternal levels as well as maternal pre-pregnant BMI. Furthermore, infantile fipronil sulfone levels were inversely associated with cord blood T3 and free T3 levels as well as 5-min Apgar scores of newborn infants.Serum fipronil sulfone was detected in a specific population of mother-neonate pairs and their matched biological fathers in a manner suggestive of regular exposure to fipronil among urban residents. The findings also suggest that serum fipronil sulfone placentally transfers to the fetus and affects infantile adverse health outcomes. This is a first of its kind study; therefore, future studies are warranted.