Substituted spiro [2.3'] oxindolespiro [3.2″]-5,6-dimethoxy-indane-1″-one-pyrrolidine analogue as inhibitors of acetylcholinesterase

Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound 4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.10 μmol/L. Pyrolidine analogues might be potential acetyl cholinesterase agents for AD.     

Bromophenols as inhibitors of protein tyrosine phosphatase 1B with antidiabetic properties

A series of bromophenol derivatives were synthesized and evaluated as protein tyrosine phosphatase 1B (PTP1B) inhibitors in vitro and in vivo based on bromophenol 4e (IC(50)=2.42 μmol/L), which was isolated from red algae Rhodomela confervoides. The results showed that all of the synthesized compounds displayed weak to good PTP1B inhibition at tested concentration. Among them, highly brominated compound 4g exhibited promising inhibitory activity against PTP1B with IC(50) 0.68 μmol/L, which was approximately fourfold more potent than lead compound 4e. Further, compound 4g demonstrated high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). More importantly, in vivo antidiabetic activities investigations of compound 4g also demonstrated inspiring results.     

Synthesis, antiproliferative, and antiplatelet activities of oxime- and amide-containing quinolin-2(1H)-one derivatives

Certain oxime- and amide-containing quinolin-2(1H)-one derivatives were synthesized and evaluated for their antiproliferative and antiplatelet activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with NH(2)OH or NaN(3) (Schmidt reaction). The preliminary assays indicated that amide derivatives are either weakly active or inactive while the oxime counterparts exhibited potent inhibitory activities against platelet aggregation induced by collagen, AA (arachidonic acid), and U46619 (the stable thromboxan A(2) receptor agonist). Among them, (Z)-6-[2-(4-methoxyphenyl)-2-hydroxyiminoethoxy]quinolin-2(1H)-one (7c) was the most active against AA induced platelet aggregation with an IC(50) of 0.58microM and was inactive against cell proliferation. For the inhibition of U46619 induced aggregation, 7a and 8a-c exhibited very potent activities with IC(50) values in a range between 0.54 and 0.74microM. For the antiproliferative evaluation, N-(biphenyl-4-yl)-2-(2-oxo-1,2-dihydroquinolin-7-yloxy)acetamide (11d) was the most potent with GI(50) values of <10, 10.8, and <10microM against the growth of MT-2, NCI-H661, and NPC-Tw01, respectively, and possessed only a weak antiplatelet activity. Further evaluation of 11d as a potential anticancer agent is on-going.     

佛波醇制备工艺优化及其衍生物的合成表征与细胞毒活性研究

目前佛波醇制备过程比较繁琐,本研究首先对制备工艺进行优化,使制备周期缩短至3天。然后以佛波醇、二十碳五烯酸、二十二碳六烯酸、花生酸为原料,设计合成了18个新化合物,运用1H NMR,13C NMR,HR-MS对化合物进行结构表征,并测试了这些化合物对人正常胚肺成纤维细胞(MRC-5)的毒性。结果显示13个化合物对正常细胞毒性较大(IC50<38.12μmol/L),5个化合物毒性较小(IC50> 100μmol/L)。佛波醇的12位羟基、13位羟基分别与长链饱和脂肪酸形成单酯时毒性较低,实验结果为佛波醇的结构修饰提供参考。     

The evaluation and structure-activity relationships of 2-benzoylaminobenzoic esters and their analogues as anti-inflammatory and anti-platelet aggregation agents

Forty-seven 2-benzoylaminobenzoic esters were synthesized and evaluated in anti-platelet aggregation, inhibition of superoxide anion generation, and inhibition of neutrophil elastase release assays. Most 2-benzoylamino-4-chlorobenzoic acid derivatives showed selective inhibitory effects on arachidonic acid (AA)-induced platelet aggregation. Among them, compounds 6b and 7b exhibited more potent inhibitory effects (ca. 200-fold) than aspirin. Additionally, compounds 1a and 5a showed strong inhibitory effects on neutrophil superoxide generation with IC(50) values of 0.65 and 0.17 microM, respectively. However, compounds 6d and 6e exhibited dual inhibitory effects on platelet aggregation and neutrophil elastase (NE) release; therefore, these two compounds may be new leads for development as anti-inflammatory and anti-platelet aggregatory agents.     

Synthesis of new sulfonamides as lipoxygenase inhibitors

The present study describes a convenient method for the synthesis of new lipoxygenase inhibitors, 4-(toluene-4-sulfonylamino)-benzoic acids from p-amino benzoic acid. Reaction of p-amino benzoic acid with p-toluenesulfonyl chloride provided thirteen N- and O-alkylation products 4a-4m in moderate to good yields. Lipoxygenase inhibition of newly formed sulfonamide derivatives was investigated and some of these compounds 4m, 4g, 4e, 4f and 4j showed good lipoxygenase inhibitory activities with IC(50) values ranged between 15.8 ± 0.57 and 91.7 ± 0.61 μmol whilst all other compounds exhibited mild anti-lipoxygenase activities with IC(50) values ranged between 139.2 ± 0.75 and 232.1 ± 0.78 μmol. N-alkylated products were more active against the enzyme than O-alkylated or both N- and O-alkylated ones. All synthesized sulfonamides were recrystallized in chloroform to give these title compounds which were characterized using FTIR, (1)H NMR, (13)C NMR, elemental analysis and single crystal X-ray diffraction techniques.     

Spiramine N-6,一种新的抗血小板和抗血小板-中性粒细胞相互作用的物质

Spiramine N-6属粉花秀线菊植物中提取分离的二十碳二萜生物碱。本实验采用Born,Shen和Hamburger等方法分别观察了spiramine N-6在体外和体内对兔血小板聚集功能的影响。应用荧光分光光度法测定其对血小板5-羟色胺释放反应的作用,同时评价spiramine N-6对激活的血小板与中性粒细胞之间粘附反应的影响。结果表明：spiramine N-6在体外选择性抑制血小板活化因子(PAF)诱导的血小板聚集,并呈量效关系,其IC50=26μmol／L,对花生四烯酸(AA)或腺苷二磷酸(ADP)引起的血小板聚集无明显作用;spiramine N-6静注后明显抑制PAF、AA和ADP诱导的血小板聚集。Spiramine N-6呈浓度依赖性减少AA和PAF引起血小板5-羟色胺的释放,其IC50分别为64．7和33．5μmol／L。Spiramine N-6明显阻抑激活的血小板与中性粒细胞间的粘附率,其IC50为78．6μmol／L。结果提示spiramine N-6作为二十碳二萜生物碱具有较强的抗血小板和阻抑血小板一中性粒细胞相互作用的生物活性。     

Design, synthesis, biological evaluation and molecular modeling of novel 1,3,4-oxadiazole derivatives based on Vanillic acid as potential immunosuppressive agents

In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC(50) concentration range from 1.25μM to 7.60 μM against the T cells, and the IC(50) of positive control (csa) is 2.12 μM. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC(50)=1.25 μM and 4.75 μM for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3Kγ/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3Kγ binding site in order to indicate the potential target.     

Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives

This paper describes the design, synthesis and pharmacological evaluation of new N-acylhydrazone (NAH) compounds, belonging to the N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone class (2a-p). Classical heteroaromatic ring bioisosterism strategies were applied to the previously reported N-phenylpyrazolyl-4-acylhydrazone derivative 1, elected as lead-compound due to its important anti-aggregating profile on arachidonic acid induced platelet aggregation (IC(50)=24+/-0.5 micro M), from which emerge this new series 2. These new compounds 2a-p were readily synthesized, characterized and tested on platelet aggregation assays induced by collagen (5 micro g/mL), ADP (5 micro M) and arachidonic acid (100 micro M) in rabbit citrated platelet-rich plasma. Compounds 2b, 2d, and 2h were found to be the most potent, exhibiting a significant antiplatelet activity on arachidonic acid- and collagen-induced platelet aggregation. In addition, these new antiplatelet agents are free of gastric ulcerogenic effect and presented discrete anti-inflammatory and analgesic properties. The N-para-chlorophenyltriazolyl-4-acylhydrazone compound 2h produced the highest inhibitory effect on collagen (IC(50)=21.6+/-0.4 micro M) and arachidonic acid-induced platelet aggregation (IC(50)=2.2+/-0.06 micro M), suggesting that the nature of the substituent on the phenyl ring of the N-heteroaromatic system of NAH moiety may be an important structural requirement for the improvement of antiplatelet activity, in comparison with lead-series 1.     

Metronidazole acid acyl sulfonamide: a novel class of anticancer agents and potential EGFR tyrosine kinase inhibitors

A series of novel metronidazole derivatives were recently reported as potent anticancer agents targeting EGFR and HER-2 by our group [Qian, Y.; Zhang, H. J.; Zhang, H.; Xu, C.; Zhao, J.; Zhu, H. L. Bioorg. Med. Chem.2010, 18, 4991]. Based on the previous results, we designed and synthesized a new series of metronidazole acid acyl sulfonamide derivatives and a new series of phenylacetyl benzenesulfonamide derivatives and their anticancer activities were evaluated as potential EGFR and HER-2 kinase inhibitors. Among all the compounds, compound 12 displayed the most potent inhibitory activity EGFR and HER-2 (IC(50)=0.39 μM for EGFR and IC(50)=1.53 μM for HER-2) and it also showed the most potent growth inhibitory activity against A549 and B16-F10 cancer cell line in vitro, with an IC(50) value of 1.26 μg/mL for A549 and 0.35 μg/mL for B16-F10. Docking simulation was further performed to position compound 12 into the EGFR active site to determine the probable binding model.     

Design, synthesis and biological evaluation of novel chalcone derivatives as antitubulin agents

A series of novel chalcone derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of tubulin. These compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell lines in vitro. Compound 3d showed the most potent antiproliferative activity against MCF-7 and A549 cell lines with IC(50) values of 0.03 and 0.95 μg/mL and exhibited the most potent tubulin inhibitory activity with IC(50) of 1.42 μg/mL. Docking simulation was performed to insert compound 3d into the crystal structure of tubulin at colchicines binding site to determine the probable binding model. Based on the preliminary results, compound 3d with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

含RGD模体的人白细胞介素18(IL-18)突变体的酵母表达及其抗血小板聚集活性

利用定点突变及DNA重组技术,在人白细胞介素18(IL18)cDNA序列中插入GGC序列,使IL18第39位精氨酸残基和第40位天冬氨酸残基之间插入一个甘氨酸残基,从而构建了RGD模体.此重组的cDNA序列构建入表达质粒pPIC9K,并转化Pichiapastoris酵母GS115,利用表达系统进行了高效表达.用SephadexG100凝胶过滤纯化表达产物,获得初步纯化的蛋白.对该蛋白进行了血小板聚集抑制实验和对GPⅡbⅢa与Fn结合的抑制实验.含RGD模体的重组IL18(IL18RGD)显示了较强的体外抑制血小板聚集活性,IC50=8.8μmolL;并具有与GPⅡbⅢa的竞争结合活性,IC50=8.0μmolL.该含有RGD模体的重组IL18仍保存对PBMC诱导产生IFNγ能力.结果表明,此IL18RGD嵌合体在具有抗炎,抗感染的同时增添了新的抑制血小板聚集功能.     

Synthesis, biological evaluation and molecular docking studies of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives as inhibitors of HDAC activity

In present study, a series of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (5a-8d) were designed, synthesized, and evaluated for HDAC inhibition and tumor cell antiproliferation. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyzes. Among the compounds, compound 8c showed the most potent biological activity against HCT116 cancer cell line (IC(50) of 0.42 ± 0.02 μM for HDAC-1 and IC(50)=0.62 ± 0.02 for HCT116). Docking simulation was performed to position compound 8c into the HDAC active site to determine the probable binding model. The results of antiproliferative assay and western-blot demonstrated that compound 8c with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent against HCT116 cancer cell.     

Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: a molecular hybridization approach

The chalcone-like series 1a-1g was efficiently synthesized from Morita-Baylis-Hillman reaction (52-74% yields). Compounds 1a-1g were designed by molecular hybridization based on the anti-inflammatory drug methyl salicylate (3) and the antileishmanial moiety of the Morita-Baylis-Hillman adducts 2a-2g. The 1a-1g compounds were much more actives than precursor series 2a-2g, for example, IC(50)=7.65 μM on Leishmania amazonensis and 10.14 μM on Leishmania chagasi (compound 1c) when compared to IC(50)=50.08 μM on L. amazonensis and 82.29 μM on L. chagasi (compound 2c). The IC(50) values of compound 3 (228.49 μM on L. amazonensis and 261.45 μM on L. chagasi) and acryloyl salicylate 4 (108.50 μM on L. amazonensis and 118.83 μM on L. chagasi) were determined here, by the first time, on Leishmania.     

Antiplatelet property of Curcuma longa L. rhizome-derived ar-turmerone

The antiplatelet activities of Curcuma longa L. rhizome-derived materials were measured using a platelet aggregometer and compared with those of aspirin as antiplatelet agent. The active constituent from the rhizome of Curcuma longa L. was isolated and characterized as ar-turmerone by various spectral analyses. At 50% inhibitory concentration (IC50) value, ar-turmerone was effective in inhibiting platelet aggregation induced by collagen (IC50, 14.4 microM) and arachidonic acid (IC50, 43.6 microM). However, ar-turmerone had no effect on platelet activating factor or thrombin induced platelet aggregation. In comparison, ar-turmerone was significantly more potent platelet inhibitor than aspirin against platelet aggregation induced by collagen. These results suggested that ar-turmerone could be useful as a lead compound for inhibiting platelet aggregation induced by collagen and arachidonic acid.     

Synthesis and anti-influenza activity of aminoalkyl rupestonates

A series of aminoalkyl rupestonates were designed and synthesized by reacting rupestonic acid with 1,ω-dibromoalkanes, followed by amination. All of the new compounds were bioassayed in vitro to determine their activities against influenza A (H3N2, H1N1) and B viruses. The results showed that compounds 5a-5g, which each contain a 1H-1,2,4-triazolyl moiety, were found to be the most potent set of compounds. Compound 5g was demonstrated to possess the highest inhibitory activity against influenza H3N2 and H1N1, with IC(50) values of 0.97 and 0.42 μM, respectively. Our results also indicated that compounds 2g, 3g, 4g and 5g, which contain ten-CH(2)-unit spacers between the rupestonic acid and amino functional groups, were the most potent inhibitors of influenza H1N1 among the synthesized compounds. Unfortunately, most of the synthesized compounds did not show an obvious activity against influenza B; the only exceptions were compounds 5d and 5f, which had IC(50) values of 17.3 and 3.2 μM, respectively. Compounds 4g and 5g were potent inhibitors of influenza H1N1, and they might be potentially developed as new lead anti-influenza virus compounds. Further studies of the mechanism of action are underway.     

Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines

A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity.     

Design, synthesis and structure-activity relationship (SAR) studies of 2,4-disubstituted pyrimidine derivatives: dual activity as cholinesterase and Aβ-aggregation inhibitors

A novel class of 2,4-disubstituted pyrimidines (7a-u, 8a-f, 9a-e) that possess substituents with varying steric and electronic properties at the C-2 and C-4 positions, were designed, synthesized and evaluated as dual cholinesterase and amyloid-β (Aβ)-aggregation inhibitors. In vitro screening identified N-(naphth-1-ylmethyl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (9a) as the most potent AChE inhibitor (IC(50)=5.5 μM). Among this class of compounds, 2-(4-methylpiperidin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine (9e) was identified as the most potent and selective BuChE inhibitor (IC(50)=2.2 μM, selectivity index=11.7) and was about 5.7-fold more potent compared to the commercial, approved reference drug galanthamine (BuChE IC(50)=12.6 μM). In addition, the selective AChE inhibitor N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine (7d), exhibited good inhibition of hAChE-induced aggregation of Aβ(1-40) fibrils (59% inhibition). Furthermore, molecular modeling studies indicate that a central pyrimidine ring serves as a suitable template to develop dual inhibitors of cholinesterase and AChE-induced Aβ aggregation thereby targeting multiple pathological routes in AD.     

Synthesis, biological evaluation, and molecular docking studies of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives as anticancer agents

A series of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives have been designed, synthesized and evaluated for their potential antiproliferation activity and Aurora-A kinase inhibitory activity. Among all the compounds, compound 10e possessed the most potent biological activity against HCT116 and MCF-7 cell lines with IC(50) values of 0.39±0.06μM and 0.46±0.04 μM, respectively, which were comparable to the positive control. Compound 10e also exhibited significant Aurora-A kinase inhibitory activity (IC(50)=0.16±0.03 μM). Docking simulation was performed to position compound 10e into the active site of Aurora-A kinase, in order to get the probable binding model for further study. The results of Western-blot assay demonstrated that compound 10e possessed good Aurora-A kinase inhibitory activity against HCT116. Based on the preliminary results, it is deduced that compound 10e with potent Aurora-A kinase inhibitory activity may be a potential anticancer agent.     

Synthesis and evaluation of antiplatelet activity of trihydroxychalcone derivatives

In an effort to develop potent antiplatelet agents, a series of trihydroxychalcones was synthesized and screened in vitro for their inhibitory effects on washed rabbit platelet aggregation induced by arachidonic acid (100 microM) and collagen (10 microg/ml). Of five compounds with potent inhibitory effects on arachidonic acid- and collagen-induced platelet aggregation, compound 4e was found to be the most potent. The structure-activity relationships suggested that antiplatelet activity was governed to a greater extent by the substituent on B ring of the chalcone template, and most of the active compounds had methoxy or dimethoxy groups on B ring.