Synthesis and antagonistic activities of enantiomers of cyclic platelet-activating factor analogues

Enantiomers of platelet-activating factor (PAF) antagonists, 3-(6-[O-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl)methyl ] phosphonoxy)hexylthiazolium (inner salt) (3), 3-[5-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxycarbonylamino]pentylthiazolium bromide (4) and 3-(5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2-yl) methyl]phosphonoxy)pentylthiazolium (inner salt) (5), were synthesized, starting from (2R,2R)- and (2S,2S)-tartaric acid. Antagonistic activities of these compounds against C16-PAF were measured in vitro (rabbit platelet aggregation, IC50) and in vivo (hypotension in rats, ID50). In these three enantiomeric pairs, the (3S)-(tetrahydropyran numbering) enantiomers were one order more potent than the (3R)-isomers: (2R,3S)-3a (R-74,654), IC50 0.59 microM and ID50 0.054 mg/kg, i.v.; (2S,3R)-3b, IC50 4.7 microM and ID50 0.30 mg/kg, i.v.; (2R,3S)-4a, IC50 0.20 microM and ID50 0.032 mg/kg, i.v.; (2S,3R)-4b, IC50 2.2 microM and IC40 0.21 mg/kg, i.v.; (2R,3R)-5a, IC50 1.1 microM and ID50 0.92 mg/kg, i.v.; (2S,3S)-5b (R-74,717), IC50 0.27 microM and ID50 0.064 mg/kg, i.v.     

V2O5-TiO2催化剂光催化降解2,4-二氯苯酚：催化剂载体和表面活性剂的影响

采用固态分散法成功制备了表面活性剂修饰的不同V2O5含量的二元氧化物催化剂,运用X射线衍射、漫反射光谱、红外光谱、扫描电镜和N2吸附-脱附法对该纳米复合物进行了表征,并在紫外光照射下考察了其光催化降解2,4-二氯苯酚的性能.结果表明,50 wt%, V2O5-TiO2(记为50V2O5-TiO2)表现出比单纯V2O5, TiO2和P25更高的光催化活性, V2O5和TiO2之间的相互作用会影响二元氧化物催化剂的光催化效率. CTAB和HTAB的修饰显著增加了50V2O5-TiO2样品的催化效率,其中(50V2O5-TiO2)-CTAB催化剂在反应30 min后表现出最高的2,4-二氯苯酚降解率(100%)和反应速率(2.22 mg/(L·min)).表面活性剂的加入能修饰二元氧化物中V2O5和TiO2的光学和电子性质,从而显著提高其光催化活性.     

Synthesis,Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies

A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).     

Topical 5-aminolevulinic acid-photodynamic therapy of hairless mouse skin using two-fold illumination schemes: PpIX fluorescence kinetics, photobleaching and biological effect

Light fractionation with dark periods of the order of hours has been shown to considerably increase the efficacy of 5-aminolevulinic acid-photodynamic therapy (ALA-PDT). Recent investigations have suggested that this increase may be due to the resynthesis of protoporphyrin IX (PpIX) during the dark period following the first illumination that is then utilized in the second light fraction. We have investigated the kinetics of PpIX fluorescence and PDT-induced damage during PDT in the normal skin of the SKH1 HR hairless mouse. A single illumination (514 nm), with light fluences of 5, 10 and 50 J cm-2 was performed 4 h after the application of 20% ALA, to determine the effect of PDT on the synthesis of PpIX. Results show that the kinetics of PpIX fluorescence after illumination are dependent on the fluence delivered; the resynthesis of PpIX is progressively inhibited following fluences above 10 J cm-2. In order to determine the influence of the PpIX fluorescence intensity at the time of the second illumination on the visual skin damage, 5 + 95 and 50 + 50 J cm-2 (when significantly less PpIX fluorescence is present before the second illumination), were delivered with a dark interval of 2 h between light fractions. Each scheme was compared to illumination with 100 J cm-2 in a single fraction delivered 4 or 6 h after the application of ALA. As we have shown previously greater skin damage results when an equal light fluence is delivered in two fractions. However, significantly more damage results when 5 J cm-2 is delivered in the first light fraction. Also, delivering 5 J cm-2 at 5 mW cm-2 + 95 J cm-2 at 50 mW cm-2 results in a reduction in visual skin damage from that obtained with 5 + 95 J cm-2 at 50 mW cm-2. A similar reduction in damage is observed if 5 + 45 J cm-2 are delivered at 50 mW cm-2. PpIX photoproducts are formed during illumination and subsequently photobleached. PpIX photoproducts do not dissipate in the 2 h dark interval between illuminations.     

Co-activation of Gi and Gq proteins exerts synergistic effect on human platelet aggregation through activation of phospholipase C and Ca2+ signalling pathways

Our previous studies have shown that subthreshold concentrations of two platelet agonists exert synergistic effects on platelet aggregation. Here we studied the mechanism of synergistic interaction of 5-hydroxytryptamine (5-HT) and epinephrine mediated platelet aggregation. We show that 5-HT had no or little effect on aggregation but it did potentiate the aggregation response of epinephrine. The synergistic interaction of 5-HT (1-5 microM) and epinephrine (0.5-2 microM) was inhibited by alpha2-adrenoceptor blocker (yohimbine; IC50= 0.4 microM), calcium channel blockers (verapamil and diltiazem with IC50 of 10 and 48 mM, respectively), PLC inhibitor (U73122; IC50=6 microM) and nitric oxide (NO) donor, SNAP (IC50=1.6 microM)). The data suggest that synergistic effects of platelet agonists are receptor-mediated and occur through multiple signalling pathways including the activation PLC/Ca2+ signalling cascades.     

Radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl of ascorbic acid 2-glucoside (AA-2G) and 6-acyl-AA-2G

The radical scavenging activity of the stable derivatives, which are O-substituted at the C-2 position of ascorbic acid (AA), against 1,1-diphenyl-2-picrylhydrazyl (DPPH) was evaluated in buffer under different pH conditions, and compared with those of AA and alpha-tocopherol. AA was shown to have 50% radical scavenging ability (EC50) at a concentration of 2.2 x 10(-5) M against 0.1 mM DPPH in 60% ethanol. Ascorbyl 6-palmitate, a lipophilic AA derivative which has a free endiol group and is therefore unstable, also showed potent radical scavenging activity with EC50 of 2.9 x 10(-5) M. A typical lipophilic antioxidant, alpha-tocopherol gave a similar EC50 value as that of AA. In contrast, ascorbyl 2,6-dipalmitate, AA 2-phosphate and AA 2-sulfate exhibited negligible scavenging activity. On the other hand, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G) and a series of 6-O-acyl-2-O-alpha-D-glucopyranosyl-L-ascorbic acids (6-Acyl-AA-2G) themselves exhibited the radical scavenging activity of EC50: 6.1 x 10(-5) M and 4.4 x 10(-5)-5.9 x 10(-5) M, respectively, although their activities were lower than that of AA. Among 6-Acyl-AA-2G derivatives, the EC50 values tended to decrease with increasing length of their acyl carbon group. Increasing pH of the buffer resulted in decrease in the scavenging activity of all compounds tested as expected. We speculate that the difference in the radical scavenging activity of derivatives O-substituted at the C-2 position of AA may be ascribed to the linkage type of the substituent group to the endiol-lactone resonance system and the degree of dissociation of the C-3 proton.     

Hydantoin derivatives of L- and D-amino acids: synthesis and evaluation of their antiviral and antitumoral activity

3,5-Disubstituted hydantoin (1,3-imidazolidinedione) derivatives 5a-h were prepared by base induced cyclization of the corresponding N-(1-benzotriazolecarbonyl)-L- and D-amino acid amides 4a-h. Compounds 5a-h were evaluated for their cytostatic and antiviral activities. Among all the compounds evaluated, 3-benzhydryl-5-isopropyl hydantoin (5a) showed a weak but selective inhibitory effect against vaccinia virus (EC(50) = 16 microg/mL; selectivity index: 25). 3-Cyclohexyl-5-phenyl hydantoin (5g) showed inhibitory activity against cervical carcinoma (HeLa, IC(50) = 5.4 microM) and breast carcinoma (MCF-7, IC(50) = 2 microM), but also cytotoxic effects towards human normal fibroblasts (WI 38). On the contrary, the 3-benzhydryl-5-phenyl substituted hydantoin derivative 5h showed moderate inhibitory activity towards HeLa, MCF-7, pancreatic carcinoma (MiaPaCa-2), lung carcinoma (H 460) and colon carcinoma (SW 620) (IC(50) = 20-23 microM), but no effect on WI 38.     

TPAOH处理制备的微介孔催化剂物化性质与噻吩烷基化性能研究

采用不同浓度的TPAOH溶液处理不同SiO_2/Al_2O_3物质的量比的HZSM-5分子筛,制备了微孔-介孔多级孔HZSM-5催化剂。结果表明,采用不同浓度的TPAOH溶液处理不同SiO_2/Al_2O_3物质的量比的HZSM-5分子筛能够脱出HZSM-5分子筛的骨架硅而产生介孔,介孔孔径随TPAOH溶液浓度和SiO_2/Al_2O_3物质的量比的增大而增大;TPAOH溶液处理能够调变HZSM-5催化剂的酸性。采用不同浓度的TPAOH溶液处理SiO_2/Al_2O_3物质的量比分别为50、80和150的HZSM-5分子筛,其中,SiO_2/Al_2O_3物质的量比为50的HZSM-5弱中酸酸强度、相对酸量、B酸和L酸含量明显高于SiO_2/Al_2O_3物质的量比为80和150的HZSM-5分子筛。经不同浓度的TPAOH溶液处理后SiO_2/Al_2O_3物质的量比为50的HZSM-5催化剂具有最佳的噻吩烷基化反应性能。     

Cytotoxicity of new 5-phenyl-4,5-dihydro-1,3,4-thiadiazole analogues

A series of 5-phenyl-4,5-dihydro-1,3,4-thiadiazoles were synthesized and their cytotoxicity was examined against four human cancer cell lines, e.g. lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), and colon cancer (HCT15). The title compounds were synthesized by condensation of thiosemicarbazide with substituted benzaldehydes, followed by cyclization with acetic anhydrides in good yields. Most of the compounds exhibited significant suppressive activity against the growth of all of the cancer cell lines. The 4-hydroxy analogue of 5-phenyl-4,5-dihydro-1,3,4-thiadiazole (2h) was most active in the inhibition of growth of the SK-MEL-2 cell line, with an IC(50) value of 4.27 μg/ml; followed by compound 2a (IC(50) 5.16 μg/ml). The compounds 2j, 2h, and 2b, bearing 3-methoxy-4-hydroxy-, 4-hydroxy- and 4-methyl substituents in the C-5 phenyl ring respectively, exhibited the highest activity against the SK-OV-3 (IC(50) 7.35 μg/ml), HCT15 (IC(50) 8.25 μg/ml) and A549 (IC(50) 9.40 μg/ml) cell lines, respectively. A structure-activity relationship study revealed that an optimal electron density on the C-5 phenyl ring of 1,3,4-thiadiazoles is crucial for their cytotoxic activity against the human cancer cell lines used in the present study.     

含50-100at%Pd的Ce-Pd系相图

本文通过X射线衍射实验证实了CePd5化合物的结构, 进一步研究了含50-100at%Pd的Ce-Pd系相图, 在750℃以上含50-100at%Pd的Ce-Pd系相图中共有5个中间化合物:CePd5, CePd3, Ce2Pd3, Ce3Pd4和CePd。     

Dioscorone. Regioselective Oxxmercuration of 2-Azabicyclo[2. 2]oct-5-ene

Oxymercuration of 2-azabicylo[2.2.2]oct-5-ane 1 occurs regioselectively to give a50:50 mixture of 5-syn-and 5-anti-isoquinculidinols 2 which can be converted to dioscorone 5.     

High-performance liquid chromatographic analysis of 5-ethylpyrimidines and 5-methylpyrimidines in plasma

A high-performance liquid chromatographic (HPLC) method employing a C18 reversed-phase column, a mobile phase of sodium acetate and methanol, and an ultraviolet detector was developed for the analysis of 5-ethylpyrimidines and 5-methylpyrimidines in plasma. Samples were prepared for HPLC by sequential cation-exchange and anion-exchange column chromatography. Linear standard curves were obtained for samples containing 0.05-50 micrograms/ml 5-ethyl-2'-deoxyuridine and 5-ethyluracil, 0.05-10 micrograms ml 5-(1-hydroxyethyl)uracil, and 0.1-50 micrograms/ml thymidine, thymine and 5-hydroxymethyluracil. Applicability of the method to determination of the kinetics of 5-ethyl-2'-deoxyuridine elimination by the isolated perfused rat liver was demonstrated; clearance of the drug was 1.29 ml/min.     

Inhibition on HIV-1 integrase activity and nitric oxide production of compounds from Ficus glomerata

An ethanol Ficus glomerata wood extract and its purified components were investigated for their HIV-1 integrase (IN) and nitric oxide (NO) inhibitory activities. From bioassay-guided isolation, five compounds: beta-sitosterol-D-glucoside (1), aloe-emodin (2), genistein (3), 1,3,6-trihydroxy-8-methyl-anthraquinone (4) and 3-(1-C-beta-D-glucopyranosyl)-2,6-dihydroxy-5-methoxybenzoic acid (5) were isolated. Among the tested samples, at concentrations of 100 microM; compound 2 showed 31.9% inhibition of HIV-1 IN, followed by 4 (19.5%), whereas other compounds were inactive. With regard to the inhibitory effect on NO production, 3 possessed the highest activity with an IC50 value of 27.5 microM, followed by 4 (IC50 = 34.7 microM) and 2 (IC50 = 41.8 microM), respectively. This is the first time that compounds 2-5 have been isolated from Ficus glomerata.     

Chlorine anion encapsulation by molecular capsules based on cucurbit[5]uril and decamethylcucurbit[5]uril

Three barrel-shaped artificial molecular capsules 1-3, based on normal cucurbit[5]uril (Q[5]) and decamethylcucurbit[5]uril (Me10Q[5]), were synthesized and structurally characterized by single-crystal X-ray diffraction. Encapsulation of a chlorine anion in the cavity of a Q[5] or Me10Q[5] to form closed a molecular capsule with the coordinated metal ions or coordinated metal ions and water molecules in the crystal structures of these compounds is common. The three complexes [Pr2(C30H30N20O10)Cl3(H2O)13]3+ 3 Cl- x 5 H2O (1), [Sr2(C40H50N20O10)(H2O)4Cl]3+ 3 Cl- x 2 (HCl) 19 H2O (2) and [K(C40H50N20O10)(H2O)Cl] x [Zn(H2O)2Cl2] x [ZnCl4]2- x 2 (H3O)+ x 8 H2O (3) all crystallize as isolated molecular capsules.     

N-monocarbamoyl derivatives of symmetrical diamines with antiviral activity

Some new N-monocarbamoyl symmetrical diamines have been prepared by the addition of symmetrical amines to isocyanates or isothiocyanates. 2,6-Diaminopyridine (1), (1R,2R)-1,2-diaminocyclohexane [(1R,2R)-2], meso-1,2-diaminocyclohexane (meso-2), or (1R,2R)-1,2-diphenylethylenediamine (3) were used as the starting symmetrical diamine frameworks. All of the newly synthesized compounds were subjected to an evaluation of antiviral activity with herpes simplex virus (HSV)-1. N-Monocarbamoyl 2,6-diaminopyridines (5a, b) showed significant antiviral activity (EC(50)=17.0, 6.2 microg/ml) comparable to that of N-monododecanoyl 2,6-diaminopyridine (A2). As a result, compound 5a showed a better selectivity index (CC(50)/EC(50) = ca. 10.0) than that of A2.     

氟脲嘧啶自旋标记衍生物的合成与抗肿瘤活性（Ⅲ）

合成了９个新的５－氟脲嘧啶自旋标记衍生物２、５ａ－ｃ和７ａ－ｃ，经元素分析、ＩＲ、ＵＶ、ＭＳ和ＥＳＲ确定了其组成和结构，对化合物２和５ａ－ｃ进行了抗小艾氏腹水肉瘤Ｓ１８０的体内筛选，初步试验结果表明：化合物５ｃ对两种瘤株均显示较强的抑制作用，其抗肿瘤活性与５－氟脲嘧啶相似，而５ｃ（ＬＤ５０＝９４４．８ｍｇ／ｋｇ）的急性毒性比５－氟脲嘧啶（ＬＤ５０＝１１７．２ｍｇ／ｋｇ）降低约８倍。     

Ni-Fe催化剂乙醇部分氧化制氢的研究

研究了Ni Fe催化剂对乙醇部分氧化制氢反应,系统地考察了不同O2/C2H5OH摩尔比及反应温度下催化剂的性能.发现Ni Fe催化剂对乙醇部分氧化制氢具有较好的催化活性,其中组成为Ni50Fe50催化剂最好,最佳的反应条件是O2/C2H5OH=1.0,T=573 K.XRD谱图表明催化剂主要由尖晶石结构的铁酸盐和FeNi3合金相组成. XPS结果说明,催化剂体相以还原态FeNi3合金相为主,表面以氧化态的铁酸盐为主.稳定性考察的结果表明,催化剂经40 h反应后,对氢的选择性明显下降,此时对应的FeNi3物相衍射峰强度也明显降低,表明催化剂对H2选择性的下降与FeNi3物相的转变有关.     

Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide derivatives

A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC(50) = 1.4 μM) compared with sorafenib (IC(50) = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC(50) = 22.6 μM).     

New parasite inhibitors encompassing novel conformationally-locked 5'-acyl sulfamoyl adenosines

We describe the design, synthesis and biological evaluation of conformationally-locked 5'-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3'-endo, North-type) nucleosides have been synthesized by covalently attaching a 4'-CH(2)-O-2' bridge () across C2'-C4' of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free-energy of stabilization of the complex leading to improved potency. Conformationally-locked 5'-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC(50) = 0.25-0.51 μM. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC(50) = 0.25 μM) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC(50) >4 μM) and in diploid human fibroblasts MRC-5 cell lines (CC(50) 4 μM). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5' can modulate the toxicity of 5'-O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization.