Preparation of (±)-2-(2,3-2H2)Jasmonic Acid and Its Methyl Ester,Methyl (±)-2-(2,3-2H2)Jasmonate

For use as the internal standards in a quantitative analysis of natural jasmonic acid (JA) and methyl jasmonate (JAMe) by gas chromatography-mass spectrometry-selected ion monitoring, (±)-2-(2,3–²H₂)JA and its methyl ester, (±)-2-(2,3–²H₂)JAMe, were efficiently prepared from 2-(2–pentyl)-2-cyclopentenone through catalytic semi-deuteriogenation of acetylenic intermediates with deuterium gas in pyridine.     

TYRO3~(-/-)AXL~(-/-)MER~(-/-)小鼠骨髓细胞mRNA的差异表达谱

TYRO3、AXL和MER受体是受体酪氨酸激酶亚家族之一,广泛地表达在哺乳动物神经、免疫、生殖、血液等系统多种细胞中,促进细胞存活、增殖和分化。本研究利用基因芯片技术筛选基因敲除的TYRO3~(~(-/-))AXL~(-/-)MER~(-/-)小鼠骨髓细胞中差异性表达的m RNA,并进行生物信息学分析。与正常小鼠骨髓细胞相比,TYRO3~(-/-)AXL~(-/-)MER~(-/-)小鼠骨髓细胞中差异表达基因探针共1 363条,其中表达上调的基因探针499条、下调的基因探针864条。GO功能富集分析发现上调的基因主要参与免疫反应,下调的基因主要参与造血。KEGG Pathway富集分析发现上调的基因主要参与细胞粘附分子和抗原呈递等信号通路。Real-time PCR验证5个差异基因,与芯片中表达变化趋势一致。因此TYRO3、AXL和MER受体共同参与调控机体的免疫反应和血细胞分化。     

(S)-3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2-(piperazin-1-yl)propanoic acid compounds: Synthesis and biological evaluation of dual PPARα/γ agonists

A series of novel, potent PPARα/γ dual agonists were synthesized and appraised. The most potent analogue, compound 2b demonstrated EC₅₀ value of 0.012 ± 0.002 and 0.032 ± 0.01 μM, respectively, for hPPARα and hPPARγ in transactivation assay. Additionally, compound 2b demonstrated good glucose and lipid lowering effect in genetic diabetic (db/db) mice.     

Synthesis of 7-(tetrahydropyran-2-yl)- and 7-(4-acetoxytetrahydropyran-2-yl)-ε-rhodomycinone and 7-(tetrahydropyran-2-yl)-ε-pyrromycinone

The ¹³C.n.m.r spectra of water-soluble and -insoluble glucans synthesized by enzymes isolated from six strains of Streptococcus mutans are interpreted. The glucans are shown to be composed primarily of α(1→3)- and α-(1→6)-linked glucosyl residues, and the relative abundance of each linkage is estimated from peak areas. Treatment of water-insoluble glucans with dextranase is found to result in water-soluble and -insoluble products, the former enriched in α-(1→6)-linkages and the latter in α-(1→3)-linkages. The structural conclusions arrived at by ¹³C-n.m.r. spectroscopy are consistent with data from methylation analysis and ¹H-n.m.r. spectroscopy.     

Synthese von O-(3-desoxy-α-d-manno-2-octulopyranosylonsäure)-(2→4)-O-(3-desoxy-α-d-manno-2-octulopyranosylonsäure)- (2→6)-O-(2-amino-2-desoxy-β-d-glucopyranosyl)-(1→6)-2-amino-2-desoxy-d-glucopyranose

Benzyl-3-O-benzyl-2-benzyloxycarbonylamino-6-O-[2-benzyloxycarbonyl-amino-2-deoxy-3,4-O-(tetraisopropyldisiloxane-1,3-diyl)- β-d-glucopyranosyl]-2-deoxy-α-d-glucopyranoside was coupled with methyl (4,5,7,8-tetra-O-acetyl-3-deoxy-α-d-manno-2-octulopyranosyl bromide)onate (13) to yield the α-glycosidically linked trisaccharide. After deacetylation and selective introduction of a second 7′,8′-O-tetraisopropyldisiloxane group, a further glycosidation reaction with 13 led regioselectively to the tetrasaccharide benzyl O-[methyl (4,5,7,8-tetra-O-acetyl-3-deoxy-α-d-manno-2-octulopyranosyl)onate]-(2→4)-O-{methyl [3-deoxy-7,8-O-(tetraisopropyldisiloxane-1,3-diyl)-α-d-manno-2-octulopyranosyl]-onate}-(2→6)-O- [2-benzyloxycarbonylamino-2-deoxy-3,4-O-(tetraisopropyldisiloxane-1,3-diyl)-β-d-glucopyranosyl]- (1→6)-3-O-benzyl-2-benzyloxycarbonyl-amino-2-deoxy-α-d-glucopyranoside. A series of deblocking steps gave O-(3-deoxy-α-d-manno-2-octulopyranosylonic acid)-(2→4)-O-(3-deoxy-α-d-manno-2-octulopyranosylonic acid)- (2→6)-O-(2-amino-2-deoxy-β-d-glucopyranosyl)-(1→6)-2-amino-2-deoxy-d-glucopyranose which was identical with a tetrasaccharide that had been isolated by hydrazinolysis of the lipopolysaccharide from Salmonella minnesota R 595. Hence, synthetic proof is provided for the linkages in this part of the inner core region of lipopolysaccharides.     

LC-MS/MS测定舒必利原料药中基因毒性杂质(E)-1-乙基-2-(硝基亚甲基)吡咯烷

建立一种可测定舒必利原料药中基因毒性杂质(E)-1-乙基-2-(硝基亚甲基)吡咯烷的液相色谱-串联质谱法(LC-MS/MS)。采用ZORBAX Eclipse XDB-Phenyl型(4.60 mm×150 mm, 5.0μm)色谱柱,以甲醇-甲酸水溶液(甲酸体积分数为0.01%)为流动相进行梯度洗脱,柱温30℃,流速0.8 mL/min。采用电喷雾离子源、正离子模式、多重反应监测模式。结果表明：(E)-1-乙基-2-(硝基亚甲基)吡咯烷在7.5～30 ng/mL范围内线性均呈现良好水平,检测限质量浓度1.50 ng/mL;定量限质量浓度3.00 ng/mL;杂质限度浓度分别为30%、100%和120%,平均回收率分别为98.09%、94.27%和97.78%;精密度相对标准偏差(RSD)为0.20%～15.00%;不同柱温、流速和色谱柱下的耐用性良好。本方法快速灵敏、准确度高且稳定性好,可用于舒必利原料药中基因毒性杂质(E)-1-乙基-2-(硝基亚甲基)吡咯烷的测定。     

Microbiological synthesis of 5-ethyl- and (E)-5-(2-bromovinyl)-2′-deoxyuridine

Summary The title compounds were prepared by an enzymatic transdeoxyribosylation from 2 dGuo or 2 dThd to the respective heterocyclic bases, 5-ethyluracil and (E)-5-(2-bromovinyl)uracil, using the whole bacterial cells ofEscherichia coli as a biocatalyst.     

Antiangiogenic properties of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol/one analogs and their derivatives

In the past half century research efforts have defined a critical role for angiogenesis in tumor growth and metastasis. We previously reported that inhibition of a novel target, ENOX1, by a (Z)-2-benzylindol-3-ylmethylene) quinuclidin-3-ol, suppressed tumor angiogenesis. The present study was undertaken in order to establish structure-activity relationships for quinuclidine analogs. The angiogenesis inhibiting activity of a series of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ols (1a-1k), (Z)-2-benzylindol-3-ylmethylene)quinuclidin-3-ones (2a-2h), (Z)-(±)-2-(1H/N-methyl-indol-3-ylmethylene)quinuclidin-3-ols (3a-3b), and substituted (Z)-(±)-2-(N-benzenesulfonylindol-3-yl-methylene)quinuclidin-3-ols and their derivatives (4a-4d) that incorporate a variety of substituents in both the indole and N-benzyl moieties was evaluated using Human Umbilical Vein Endothelial Cells (HUVECs) subjected to in vitro cell migration scratch assays, tubule formation in Matrigel, cell viability and proliferation assays. In total, 25 different analogs were evaluated. Based on in vitro cell migration scratch assays, eight analogs were identified as potent angiogenesis inhibitors at 10 μM, a concentration that was determined to be nontoxic by colony formation assay. In addition, this approach identified a potent antiangiogenic ENOX1 inhibitor, analog 4b.     

Synthesis of (2′S)-1-(2-C-Azidomethyl-2-deoxy and 2-C-Cyanomethyl-2-deoxy-β-D-arabinofuranosyl)cytosines

Abstract

2′-C-Cyanomethyl-2′-deoxy-arabinosylcytosine 3 and 2′-C-azidomethyl-2′-deoxy-arabinosylcytosine 4 were synthesized from uridine. The antineoplastic activities of these compounds were evaluated.     

New imidazoline/α(2)-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies

Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/??₂-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and ??₂-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I₁, I₂, ??₂-adrenoceptors affinities are reported.     

2′-(E)-O-p-coumaroylgalactaric acid and 2′-(E)-O-feruloylgalactaric acid in citrus

2′-(E)-O-p-Coumaroyl- and 2′-(E)-O-feruloylgalactaric acids, hitherto unknown in nature, have been isolated and identified from orange peel.     

Structure–activity relationship (SAR) studies of 3-(2-amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione: Development of potential substrate-specific ERK1/2 inhibitors

A series of analogs of 3-(2-amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione, a putative substrate-specific ERK1/2 inhibitor, were synthesized and biologically characterized in human leukemia U937 cells to define its pharmacophore. It was discovered that shift of ethoxy substitution from the 4- to the 2-position on the phenyl ring significantly improved functional activities of inhibiting cell proliferation and inducing apoptosis. This may provide access to a new lead for developing ERK1/2 substrate-specific inhibitors.     

Crystal structures, spectral and magnetic properties of cobalt(II) pyridinecarboxylates: A novel polymeric chain in {[{2,6-(MeO)2nic}2(H2O)2Co(μ-H2O)Co(H2O)4(μ-H2O)]{2,6-(MeO)2nic}2 · 6H2O}n

Synthesis and characterization of two new cobalt(II) complexes, namely monomeric [Co(2-MeSnic)₂(H₂O)₄] · 4H₂O (2-MeSnic is 2-methylthionicotinate) and polymeric {[{2,6-(MeO)₂nic}₂(H₂O)₂Co(μ-H₂O)Co(H₂O)₄(μ-H₂O)]{2,6-(MeO)₂nic}₂ · 6H₂O}_n (2,6-(MeO)₂nic is 2,6-dimethoxynicotinate), are reported. The characterizations were based on elemental analysis, infrared and electronic spectra as well as magnetic measurements. Crystal structures of both complexes have been determined. In both of them - ([Co(2-MeSnic)₂(H₂O)₄] · 4H₂O and {[{2,6-(MeO)₂nic}₂(H₂O)₂Co(μ-H₂O)Co(H₂O)₄(μ-H₂O)]{2,6-(MeO)₂nic}₂ · 6H₂O}_n) - the Co^II atom is six-coordinated. In the 2nd complex, there are two nonequivalent Co^II central atoms, involved in forming a linear polymeric chain with alternating cationic and neutral part. One of them is octahedrally coordinated by a carboxyl oxygen atom of 2,6-(MeO)₂nic, two water molecules and the corresponding centrosymmetrically located atoms. The second Co^II atom is also octahedrally coordinated by six water molecules. Both coordination polyhedra are bridged by a water molecule. The charge of the cationic part is compensated for by two independent anionic 2,6-(MeO)₂nic units. The structure is held together by a complicated system of hydrogen bonds.     

Synthetic mucin fragments. Methyl 6-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,methyl 3,4-di-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,and methyl O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1 å 3)-O-β-D-galactopyranosyl-(1 å 3)-O-(2-acetamido-2-deoxy-β- D-glucopyranosyl)-(1 å 3)-β-D-galactopyranoside

Condensation of methyl 2,6-di-O-benzyl-β-d-galactopyranoside with 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-d-glucopyrano)-[2,1,-d]-2-oxazoline (1) in 1,2-dichloroethane, in the presence of p-toluenesulfonic acid, afforded a trisaccharide derivative which, on deacetylation, gave methyl 3,4-di-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2,6-di-O-benzyl-β-d- glactopyranoside (5). Hydrogenolysis of the benzyl groups of 5 furnished the title trisaccharide (6). A similar condensation of methyl 2,3-di-O-benzyl-β-d-galactopyranoside with 1 produced a partially-protected disacchraide derivative, which, on O-deacetylation followed by hydrogenolysis, gave methyl 6-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-β-d-glactopyranoside (10). Condensation of methyl 3-O-(2-acetamido-4,6-O-benzylidene-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-benzyl-β-d- galactopyranoside with 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-acetyl-α-d-galactopyranosyl bromide in 1:1 benzene-nitromethane in the presence of powdered mercuric cyanide gave a fully-protected tetrasaccharide derivative, which was O-deacetylated and then subjected to catalytic hydrogenation to furnish methyl O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→3)-O-β-d-galactopyranosyl-(1å3)-O-(2-acetamido-2-deoxy- β-d-glucopyranosyl)-(1å3)-β-d-galactopyranoside (15). The structures of 6, 10, and 15 were established by ¹³C-n.m.r. spectroscopy.     

ApoE~(-/-)小鼠动脉粥样硬化模型的建立

ApoE-基因敲除小鼠(ApoE-/-)经含有21%脂肪和0.15%胆固醇的高脂饲料喂食12周后进行各项血脂胆固醇水平检测,以及整体主动脉油红O染色与主动脉根部病理切片油红O染色等动脉粥样硬化病理分析。结果显示经过高脂诱导的ApoE-/-小鼠的血浆总胆固醇和甘油三酯水平均比未经饮食诱导的ApoE-/-小鼠、经同样饮食处理的野生型小鼠以及未经处理的野生型小鼠均显著升高(P0.05);低密度脂蛋白-胆固醇水平与野生型(正常饮食组和高脂组)相比升高了近3倍多;高脂诱导ApoE-/-小鼠的主动脉斑块面积占整体主动脉面积的65%,显著高于ApoE-/-小鼠的正常饮食组(21%)(P0.05),同时主动脉根部的血管壁明显增厚,管腔变窄。实验结果表明通过高脂饲料饮食诱导,成功建立了动脉粥样硬化模型小鼠,可为下游的药物筛选、基因治疗以及动脉粥样硬化机理的体内研究提供理想的实验材料。     

Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women. Apart from estrogenic induction, aberrant activation of the Wnt/β-catenin signal is well known to correlate with endometrial hyperplasia and its carcinoma. The benzopyran compound 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo (b) pyran(K-1), a potent antiestrogenic agent, has been shown to have apoptosis-inducing activity in rat uterine hyperplasia. The current study was undertaken to explore the effect of the benzopyran compound K-1 on growth and Wnt signaling in human endometrial hyperplasial cells. Primary culture of atypical endometrial hyperplasial cells was characterized by the epithelial cell marker cytokeratin-7. Results revealed that compound K-1 reduced the viability of primary endometrial hyperplasial cells and expression of ERα, PR, PCNA, Wnt7a, FZD6, pGsk3β and β-catenin without affecting the growth of the primary culture of normal endometrial cells. The β-catenin target genes CyclinD1 and c-myc were also found to be reduced, whereas the expression of axin2 and Wnt/β-catenin signaling inhibitor Dkk-1 was found to be upregulated, which caused the reduced interaction of Wnt7a and FZD6. Nuclear accumulation of β-catenin was found to be decreased by compound K-1. K-1 also suppressed the pPI3K/pAkt survival pathway and induced the cleavage of caspases and PARP, thus subsequently causing the apoptosis of endometrial hyperplasial cells. In conclusion, compound K-1 suppressed the growth of human primary endometrial hyperplasial cells through discontinued Wnt/β-catenin signaling and induced apoptosis via inhibiting the PI3K/Akt survival pathway.Wnt/β-catenin signaling is known to have a prominent role in a number of developmental processes,¹ differentiation and proliferation,² survival and adhesion³ as well as the regulation of menstrual cycle.⁴ In the endometrium, Wnt/β-catenin signaling is under the control of finely tuned hormonal equilibrium, for example, estrogen induces the nuclear accumulation of β-catenin during the proliferative phase, which is later decreased during the secretary phase by progesterone, in the menstrual cycle.^{5, 6} Aberrant regulation of the Wnt signaling pathway results in neoplastic transformation and thus lays at the root of initiation and progression of many malignancies.^{7, 8} Moreover, nuclear β-catenin staining has been found to be prominent in the early onset of endometrial cancer, endometrial hyperplasia and well-differentiated endometriod carcinomas.^{9, 10}Unopposed estrogen action induces proliferative disorders and changes in the tissue structure of uterus, culminating into atypical hyperplasia and subsequently, the endometrial carcinogenesis.^{11, 12} The regression of hyperplastic to normal endometrium is the main purpose of any conservative treatment in order to prevent the development of adenocarcinoma. Currently, as a mode of treatment for hyperplasia, cyclical progestin therapy is recommended, whereas in patients with cellular atypia, hysterectomy is recommended. However, neither progestin treatment, the major hormonal therapy for endometrial cancer, nor cytotoxic chemotherapy showed substantial benefits for the treatment of endometrial hyperplasia. Therefore, future research activities must evaluate new compounds and treatment strategies.In our prior studies, it has been demonstrated that benzopyrans are the class of potent antiestrogenic compounds^{13, 14} that showed antiproliferative and apoptotic activity in rat endometrial hyperplasia¹⁵ and in human endometrial cancer cells.^{16, 17} However, the complete mechanism of action of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1), responsible for inhibition of endometrial hyperplasia, remains to be explored in human endometrial hyperplasial cells. Because estrogen is one of the factor responsible for inducing Wnt/β-catenin signaling that may be responsible for inducing proliferation and hyperplasia formation in endometrium,^{4, 5} we further analyzed whether the benzopyran compound (K-1) modulates Wnt/β-catenin signaling in human endometrial hyperplasial cells from proliferation (Wnt-On) to differentiation (Wnt-Off). Accordingly, in the current study, we explored the antiproliferative efficacy of K-1 on primary culture cells derived from human endometrial hyperplasial tissue and investigated the Wnt/β-catenin pathway and its downstream signaling. We have also studied the effect of K-1 on cell survival pathway to substantiate the above conjecture.     

Amphiphilic Cationic β-Cyclodextrin Derivatives Containing 2-(4-Isobutylphenyl)- and 2-(3-Benzoilphenyl) Propionic Acid Residues

Russian Journal of Bioorganic Chemistry - The synthesis of amphiphilic cationic β-cyclodextrin derivatives that contain the residues of some pharmacologically important acids have been...