Design, Synthesis and Molecular Docking of a Novel Small-molecule Inhibitor of Caspase-3

4,5-Dihydro-3-methylbenzo[1,2-b]furan-4,5-dione(4) was identified as a novel and potent inhibitor of caspase-3 through structural modification of an existing drug,sodium tanshinone ⅡA sulfonate(STS).Compound 4 showed high potency against caspase-3 in vitro(IC50=0.13 μmol/L).Molecular docking study further provided an insight into the interaction of compound 4 with activated caspase-3.Hence,this small-molecule caspase-3 inhibitor could be a promising therapeutic candidate against diseases caused by abnormally up-regulated apoptosis.     

Discovery of Fuchsone Derivatives as Novel Nonpeptide Inhibitor of Caspase-3

Many degenerative diseases caused by uncontrolled cell death can be intervened pharmaceutically through inhibiting caspase-3 activity that leads to cell apoptosis. Here is presented the discovery of rosolic acid and phe- nolphthalein methyl ester, which both belong to fuchsone derivatives, as novel and potent nonpeptide inhibitors of caspase-3. They show high inhibitory potency against caspase-3 in vitro(IC50=0.28 and 0.13 μmol/L). Molecular modeling study provided further an insight into the interaction of phenolphthalein methyl ester with activated caspase-3. The structures of the present small-molecule caspase-3 inhibitors are different from the structures of known caspase-3 inhibitors, so the inhibitors were likely to provide some information for the discovery of anti-caspase-3 inhibitors.     

新型含硫肿瘤坏死因子类肽抑制剂的合成与活性

为了发展新型TNF类肽抑制剂, 考虑到酶活性中心含有Zn²⁺离子, 我们以通式1的骨架为基础, 设计并合成了一类含有硫原子的类肽化合物2, 其具有三肽的基本骨架, 羟胺的游离羟基和侧链上的硫原子均可与金属蛋白酶活性中心的Zn²⁺络合, 起抑制活性作用.     

Caspase-3抑制剂研究进展

Caspase-3是细胞凋亡的关键酶和执行者,研究开发Caspase-3抑制剂对于阐明许多重要疾病,提供治疗方案以及开发新型农药、兽药都具有潜在应用价值.通过计算机辅助分子设计、高通量筛选等先进方法技术,近来国内外发现了许多类型各异的高活性Caspase-3抑制剂,不少化合物活性达到了纳摩尔级.本文从合成肽类抑制剂、合成非肽类抑制剂、天然肽类抑制剂、天然非肽类抑制剂角度对近年来国内外Caspase-3抑制剂研究进展进行了综述,旨在为相关研究提供参考.     

新型多巴胺D3受体抑制剂的发现

根据最新解析的多巴胺D3受体的晶体结构进行活性位点分析, 建立了基于受体的药效团模型, 并对Asinex Gold Collection 数据库进行筛选, 选择7个化合物进行生物活性测试, 得到了高活性新型多巴胺受体抑制剂(04932482), 它对多巴胺D3受体抑制率达85.45%, 其Ki值为(806.75±34.58) nmol/L. 进一步对活性化合物进行结构分析, 研究了其与受体相互作用的模式, 并以此为指导提出以04932482为先导化合物进行结构改造的方向.     

Enantioselective Syntheses of Plate Let-Activating Factor and a Phospholipase A2 Inhibitor from Chiral Synthons Prepared Enzymatically

Efficient procedures have been developed for the stereospecific syntheses of platelet-activating factor and its 2-acetamido analog, an inhibitor of phospholipase A₂. (S)-3-O-Actyl-2-O-benzylglycerol and (S)-2-N-benzyloxycarbonyl-3-O-valerylserinol are used as starting materials for the syntheses. Both chiral synthons are prepared from lipase-catalyzed acetylation and hydrolysis of the corresponding meso precursors.     

Apoptosis of T-47D Cells Induced by Cinobufacini via a Caspase-3-dependent Manner

To investigate the mechanism of the anti-tumor activity of cinobufacini on the breast cancer cell line T-47D,the inhibitory effect of cinobufacini on the proliferation of T-47D was detected via MTT assay and the morphological changes of T-47D and HBL-100 cells caused by cinobufacini were observed with an inverted microscope.Cell apoptosis and cell cycle stages were detected by flow cytometry analysis.The effects of cinobufacini on the expression of active-form and pro-form of caspase-3 were assessed by Western blot analysis.Cinobufacini dramatically inhibited T-47D proliferation in a dose-and time-dependent manner.We found that more than 20％ of T-47D cells were killed after treatment with 20 mg/mL cinobufacini for 24 h in vitro.After 6 d of treatment with 20 mg/mL cinobufacini,the cell survival rate decreased by more than 40％.Flow cytometric analysis demonstrated that cinobufacini induced significant apoptosis and changes of the cell cycle distribution of T-47D cells.We used breast cell line HBL-100 as the control,the above experiments except cell cycle analysis showed that cinobufacini more obviously induced the apoptosis of T-47D cells than that of HBL-100 cells.Western blot analysis confirmed the protein expression of active caspase-3 increased with increasing the dose of cinobufacini.These results indicate that cinobufacini induces the apoptosis of T-47D cells via the up-regulation of caspase-3.     

一种新BCN化合物先驱体的合成及其表征

以三聚氰胺和硼酸为原料在水溶液中反应合成了一种新的BCN化合物先驱体, 通过元素分析、XRD、FT-IR、电喷雾质谱及单晶X射线衍射对其进行了表征. 结构分析表明该化合物属单斜晶系, 化学式为C3H6N6(H3BO3)2, 是由C3H6N6分子和H3BO3分子通过氢键加合组装成的具有三维超分子结构的化合物. 将该先驱体在1900 ℃氮气气氛下热解, 对产物进行XRD和XPS表征, 结果表明得到了含碳量较低的具有乱层石墨结构的新型B3CN3化合物.     

新型4,4-二甲基异噁唑-3-酮衍生物的合成及生物活性研究

以Baylis-Hillman加成物为起始原料,设计并合成了5个结构新颖的4,4-二甲基异唑-3-酮衍生物。所合成的化合物经IR、1HNMR和元素分析确证。生物活性测试结果表明,所合成的目标产物在2000gai/ha的剂量下均具有较好的除草活性。中间体1-(2,4-二氯苯基)-2-溴甲基丙烯酸乙酯具有杀虫活性,在600gai/ha的剂量下对朱砂叶螨防效为100%。     

Solution-phase synthesis of ICG-001, a β-turn peptidomimetic molecule inhibitor of β-catenin–Tcf-mediated transcription

The solution-phase synthesis of the β-turn peptidomimetic ICG-001, a selective inhibitor of Wnt/β-catenin signalling, which has been found to be important for both initiation and progression of cancers of different tissues and has been exploited as an extremely useful chemogenomic tool, was developed. This route is particularly suitable for the multigram scale preparation of ICG-001.     

Enantioselective Synthesis of N-[(S)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline from Chiral Synthon Prepared Enzymatically; A Practical Method for Large-Scale Synthesis

Efficient procedures have been developed for the stereospecific synthesis of Angiotensin-converting enzyme inhibitor, Enalapril. The starting material, (R)-2-hydroxy-4-phenylbutyronitrile, is prepared from lipase-catalyzed acetylation. This process is useful for multigram-scale synthesis.     

De Novo Design and Synthesis of a γ‐Turn Peptidomimetic Scaffold and Its Application as JNK3 Allosteric Ligand

As a way to develop a neuroprotective agent for the JNK3‐JIP1‐binding site, peptidomimetics of JIP‐1 as JNK3 allosteric regulators have been examined. The study consisted of in silico scaffold hopping, molecular docking, solution and solid‐phase peptide syntheses, and K_d measurements using surface plasmon resonance. As a peptidomimetic of JIP1, heptamer mimetic 16 (K_d=2.72 μm ) displayed a higher affinity than decamer JIP1 (K_d=23.6 μm ). The high affinity of 16 implies that the characteristic γ‐turn mimetic structure, “”Φ‐X‐Φ“ hydrophobic motif in 16 , increased its affinity toward the JIP‐site of JNK3.     

Design, Synthesis, and Activities of Novel Derivatives of Isophthalamide and Benzene-1, 3-disulfonamide

Introduction Themeritsofantiplatelettherapyforthepreven tionofthrombosisincardiovasculardiseaseareevi dent.Meta analysisresultshaveshownthatsecondary preventionbyantiplateletaggregationagentscanreduce theriskofnonfatalmyocardialinfarction(MI)and strokeby2…     

3-亚甲基异吲哚酮的合成新方法(英文)

亚甲基异吲哚酮衍生物2是一类重要的药物合成中间体,近来又被用作新型有机金属染料合成的配体。文献报道化合物2的主要合成方法是采用苯基锂衍生物的分子内反应,或以有机钛为主要原料合成目标产物,但以上方法原料难得,反应条件苛刻,产率不理想,难以大规模合成。我们首次发现以苯基环缩醛为原料一步法合成亚甲基异吲哚酮2的新方法,原料易得,条件温和,操作简便,产率良好,为本甲醛作起始原料合成化合物2提供了一条新途径。     

SARS冠状病毒3CL蛋白酶及其抑制剂的理论研究

应用AutoDock程序将SARS冠状病毒3CL蛋白酶及其抑制剂配体和受体进行了对接,并用InsightⅡ中的Discover 3模块进行了分子动力学模拟,分析了蛋白酶活性口袋的形状,讨论了其亚基的氢键、静电、疏水等相互作用,为进一步设计药物提供了重要的参考信息.     

Synthesis and Characterization of a Novel Zeolite CJS-4

A novel zeolite, denoted as CJS-4, has been synthesized from nonalkaline medium by using 4,4'-trimethylenebis(1-methylpiperidine) or 1,4-diazoniabicyclo(2,2,2) octane as template agent, respectively. The precursors were characterized by means of powder X-ray diffraction, scanning electron microscopy, thermal analysis, gas adsorption and high resolution solid state NMR of 13C and 29Si.     

一类新型酰基脲化合物的设计,合成及生物活性

设计并合成了２１个新型含呋喃环的双酰基脲化合物，经ＩＲ，＾１ＨＮＭＲ、ＭＳ和元素分析确证其结构，初步生物活性测定结果表明，该类化合物具有几丁质抑制活性。     

Design,Synthesis and Biological Activity of Novel Chalcone Derivatives as Anti-influenza Agents

A series of novel chalcone derivatives was designed and synthesized via a suitable synthetic strategy in good yields using commercially available 2-amino-4-nitrophenol as an initiator. The structures of the target compounds were confirmed by means of ¹H NMR, ¹³C NMR and high-resolution mass spectrometry(HRMS). And the ability of the target compounds to inhibit influenza viruses was evaluated. These compounds showed moderate inhibitory activity against influenza A(H9N2 and H5N1) viruses. Within this series, compounds S14 and S15 with good potency(IC₅₀=40.3-51.5μmol/L) could be used as lead compounds in the future.     

Synthesis of Novel Isoxazole-contained Analogues of Losartan

Losartan 1 (Dup-753) is a nonpeptide angiotensin II receptor (type AT1) antagonist discovered by Duncia, J.V. et al. 1 in 1990 and its potassium salt (cozaar) has been marketed as an antihypertensive since 1995 2. 1 2 Starting from Dup-753, a great number of structural related compounds have been prepared by several laboratories and several antihypertensive drugs have been developed3. In order to find new and more active compounds, a novel type of Losartan analogues 2 was designed and syn…     

Synthesis and cytotoxicity studies of quinoline-3-carbonitrile derivatives

<正>A series of quinoline-3-carbonitrile derivatives were designed and synthesized.Their cytotoxicity in vitro against four cancer cell lines(A549,HT-29,MDA-MB-231 and SMMC-7721) were evaluated by standard MTT assay.The pharmacological results showed that most of the prepared compounds displayed excellent selective cytotoxicity toward SMMC-7721 cell line.Among them, compounds 7c,7e,11b,11f and 11g were more active than Gefitinb against SMMC-7721 cell line.