新型京尼平衍生物的合成、表征及抗糖尿病活性

为了寻找新型的抗糖尿病分子,从京尼平出发,经过甲基化（苄基化）、甲磺酰基取代、叠氮基取代和还原等4步反应得到含有活泼胺基的2个母核化合物. 这2个母核化合物与不同的酰氯反应,共得到13个新的京尼平衍生物,总收率41%~63%,其结构经核磁共振、质谱和元素分析确认. 活性测试结果表明,所有目标化合物在10 mmol/L 浓度下都有一定的抗糖尿病活性,其中化合物10f对二肽基肽酶4（DPP Ⅳ）的抑制率达31.2%.     

新型咪唑-查尔酮衍生物的设计、合成及抗宫颈癌和顺铂耐药活性研究

摘要 目的 以甘草查尔酮母核为先导化合物骨架,设计、合成一系列新型咪唑-查尔酮衍生物并进行抗宫颈癌活性研究。方法 在查尔酮骨架的B环引入4种咪唑环,在A环分别引入甲氧基、氨基、羟基等活性基团;采用Claisen-Schmidt反应合成系列新型咪唑-查尔酮衍生物,其结构经1H-NMR、13C-NMR和HRMS进行表征。通过MTT、Transwell、流式细胞仪和分子对接实验方法,初步探索目标化合物的抗宫颈癌活性及作用机制。结果 大部分化合物具有一定的抗宫颈癌活性,其中2i较为显著,且对正常细胞的毒性较小。此外,化合物2i能够显著抑制HeLa和HeLa/DDP细胞的迁移和侵袭能力,能够诱导其凋亡,并阻滞HeLa和HeLa/DDP细胞于G2/M期;分子对接模拟显示2i与查尔酮母核和原配体秋水仙碱相比,2i与微管蛋白秋水仙碱结合位点具有较好的结合能力,并能够产生氢键相互作用力。结论 化合物2i具有较显著的抗宫颈癌和抗宫颈癌顺铂耐药活性作用,这可能与其抑制了微管蛋白靶点有关。     

莽吉柿中几种双苯吡酮和蒽醌类成分的分离与鉴定

对莽吉柿(Pericarpium Garciniae Mangostanae)85%乙醇提取物进一步分离,得到8个双苯吡酮类化合物和1个蒽酮类化合物,经理化性质和NMR及MS谱学数据鉴定分别为α-倒捻子素-3,6-二乙酸酯（α-mangostin-3,6-diyl diacetate,Ⅰ）、1,5,8-三羟基-3-甲氧基-2,4-双-（3-甲基丁-2-烯）双苯吡酮（8-hydroxycudraxanthone G,Ⅱ）、1,3-二羟基-6,7-二甲氧基-2,8-双-（3-甲基丁-2-烯基）双苯吡酮（Cowaxanthone B,Ⅲ）、1,6-二羟基-3,5-二甲氧基-2-（3-甲基丁-2-烯基）双苯吡酮（Cowaxanthone A,Ⅳ）、1,5-二羟基-4-（3-甲基丁-2-烯基）-6′,6′-二甲基吡喃[2′,3′:3,2]双苯吡酮（trapezifolixanthone,Ⅴ）、1,6-二羟基-6′,6′-二甲基吡喃[2′,3′:7,8]-6″,6″-二甲基吡喃[2″,3″:3,2-]双苯吡酮（brasilixanthone B,Ⅵ）、1,3,5-三羟基-2-（3-甲基丁-2-烯）-4-（1,1-二甲基-2-烯丙基）双苯吡酮（Allanxanthone A,Ⅶ）、1,3,8-三羟基-5-甲氧基-2,4-双-（3-甲基丁-2-烯）双苯吡酮(2,4-di-(3-methylbut-2-enyl)-1,3,8-trihydroxy-5-methoxyxanthone,Ⅷ)、1,4,8-三羟基-6-甲基-3-甲氧基-9,10-蒽酮(1,4,8-trihydroxy-6-methyl-3-methoxy- 9,10-anthraquinone, Ⅸ）。 其中化合物Ⅰ、Ⅴ、Ⅵ、Ⅶ、Ⅸ为首次从藤黄属植物中分离得到,化合物Ⅱ、Ⅲ、Ⅳ、Ⅷ为首次从该植物中分离得到。     

呋喃并呫吨酮衍生物的合成与生物活性研究

以水杨酸、间苯三酚为原料合成了1,3-二羟基呫吨酮, 经醚化、环化反应得到1-羟基呋喃并呫吨酮3a和3b, 再经Mannich反应合成了10个呋喃并呫吨酮衍生物4和5, 接着通过季铵化反应得到相应的10个季铵盐6和7. 运用IR、一维和二维NMR、MS、元素分析等对化合物进行了结构表征, 考察了化合物4～7对乙酰胆碱酯酶的抑制作用及化合物6, 7的抗癌活性. 结果表明: 化合物4～7对乙酰胆碱酯酶具有较好的抑制活性, IC50＝2.0～12.4 μmol/L; 化合物6, 7对肝癌(HepG2)、肺癌(SPC-A)、口腔上皮癌(KB)、乳腺癌(MCF-7)这四种癌细胞株的增殖均有抑制作用, 其中化合物6c对癌细胞株HepG2、化合物7d对癌细胞株MCF-7的抑制作用最强, IC50分别为0.82和0.77 μmol/L.     

二肽肽酶Ⅳ抑制剂的三维定量构效关系研究

二肽肽酶Ⅳ是一类用于治疗Ⅱ型糖尿病具有潜在价值的关键酶,很多此类酶的抑制剂用于处理此病具有相当好的有效性.一系列N-取代的甘氨酰氰基吡咯烷衍生物对于二肽肽酶具有高的活性和选择性.我们使用比较分子力场分析方法建立DPP-Ⅳ抑制剂--N-取代的甘氨酰氰基吡咯衍生物的三维定量构效关系,该模型为设计用于治疗Ⅱ型糖尿病的高效DPP-Ⅳ抑制剂提供结构信息.CoMFA模型的交叉验证相关系数q2=0.575,非交叉验证相关系数r2=0.981,绝对误差S=0.184,F9.68=388.5.使用七个预测集检验了模型的预测能力.所得的模型解释了已有的构效关系,并对同类化合物有较好的预测能力,该模型可用于指导新型的DPP-Ⅳ抑制剂的设计与优化.     

立体选择性合成内型N-Boc-N-去甲托品醇

以托品酮为起始原料,与氯甲酸氯乙酯经脱甲基化反应制得脱甲基托品酮（1）; 1与Boc酸酐反应制得N-Boc-N-去甲托品酮（2）;以三仲丁基硼氢化锂为还原剂,2经还原反应立体选择性合成了内型N-Boc-N-去甲托品醇（内型/外型=6.5/1）,总收率60%,其结构经¹H NMR和ESI-MS确证。     

含尿嘧啶结构单元二肽衍生物的设计、合成及生物活性研究

为探索新型抗糖尿病分子,设计了含有尿嘧啶结构单元的二肽衍生物.以尿嘧啶、多聚甲醛和半胱氨酸为原料,经过两步反应获得关键中间体S-胸腺嘧啶-L-半胱氨酸(IM-2),再经氨基保护、羧基酯化和氨基酸偶联,顺利合成了16个二肽衍生物.所得目标化合物均经1HNMR、13CNMR和HRMS进行结构确认,并开展了过氧化物酶体增殖物受体反应元件(PPRE)激动活性、α-葡萄糖苷酶-rat抑制活性、二肽基肽酶-4 (DPP-4)抑制活性筛选.生物活性结果显示,这些二肽衍生物的PPRE相对激动活性、α-葡萄糖苷酶和DPP-4抑制活性都很弱;同时发现,该类分子的α-葡萄糖苷酶抑制活性变化趋势与PPRE激动活性、DPP-4抑制活性变化趋势相反,这为新型多肽多靶点药物的设计提供了新思路.     

新型噻唑烷二酮衍生物的合成及其抑制酪氨酸酶活性研究

以噻唑烷二酮和取代芳香醛为原料,通过缩合反应合成了一系列新型噻唑烷二酮衍生物（1~11）,其结构经¹H NMR、¹³C NMR、 IR、 MS（ESI）和元素分析表征,并考察了1~11对酪氨酸酶的抑制活性。结果表明：所有化合物都具有一定的酪氨酸酶抑制活性,部分化合物对酪氨酸酶的抑制活性强于阳性对照曲酸。初步构效关系分析表明：5-(4-羟基-3-甲氧基苯亚甲基)-2,4-噻唑烷二酮(8)抑制效果最强(IC₅₀=0.12±0.03μM)。选择化合物8进行了抑制动力学和分子对接研究。结果表明：化合物8为竞争性抑制剂,其抑制常数K_i为0.54 μM; 8能够和酪氨酸酶铜离子活性中心相互作用,从而抑制酪氨酸酶活性。      

5-取代-2-羟甲基苯酚衍生物的合成及体外抗肿瘤活性研究

以2-羟基-4-甲基苯甲酸为原料, 经过丙酮叉保护、NBS溴代制得中间体7-(溴甲基)-2,2-二甲基-4H-苯并[d][1,3]二氧六环-4-酮（4）,再分别和两种杂环仲胺发生N-烷基化反应制得化合物5a-b,最后经过四氢铝锂还原得到目标化合物1a-b,其结构经1H NMR、13C NMR和ESI-MS进行表征。同时,考察了N-烷基化反应和还原反应的反应条件,确定了N-烷基化反应的最佳条件为：物料比为n（吡唑）: n（化合物4）= 1.2 : 1;K2CO3用量为n（K2CO3）: n（化合物4）= 2.0 : 1;50℃反应5 h。最佳还原反应条件为：LiAlH4用量为n（LiAlH4）: n（化合物5a）= 1.2 : 1,-75℃反应时间为1.0 h。此外,采用了MTT法测试了所合成的化合物1a-b对HepG2,HeLa,MCF-7,A5494四种肿瘤细胞以及正常宫颈上皮细胞HUCEC的体外抑制活性。结果表明,目标化合物1a-b对HeLa细胞展现出了明显的抑制作用,其IC50分别为18.4和10.6 μmol ? L-1,而对正常的HUCEC没有抑制活性。这些结果有望为进一步开发具有抗肿瘤活性的2-羟甲基苯酚衍生物提供参考。     

内酯开环塔斯品碱香豆素酯衍生荧光化合物的合成及其抗癌活性

以异香草醛为原料,经溴代、苄基保护、氧化、Ulmman反应和还原等6步反应合成了塔斯品碱内酯开环衍生物（化合物8）。 通过在其结构中分别引入含有2种不同取代基的香豆素衍生物,设计、合成了2个新型荧光性的内酯开环塔斯品碱香豆素酯衍生物（化合物9a和9b）。 产物结构经IR、1H NMR和MS进行了表征。 同时,对产物的荧光特性及其对乳腺肿瘤细胞增殖的抑制活性进行了初步测定。     

Virtual screening of dipeptidyl peptidase-4 inhibitors using quantitative structure–activity relationship-based artificial intelligence and molecular docking of hit compounds

Dipeptidyl peptidase-4 (DPP-4) inhibitors are becoming an essential drug in the treatment of type 2 diabetes mellitus; however, some classes of these drugs exert side effects, including joint pain and pancreatitis. Studies suggest that these side effects might be related to secondary inhibition of DPP-8 and DPP-9. In this study, we identified DPP-4-inhibitor hit compounds selective against DPP-8 and DPP-9. We built a virtual screening workflow using a quantitative structure–activity relationship (QSAR) strategy based on artificial intelligence to allow faster screening of millions of molecules for the DPP-4 target relative to other screening methods. Five regression machine learning algorithms and four classification machine learning algorithms were applied to build virtual screening workflows, with the QSAR model applied using support vector regression (R²_pred 0.78) and the classification QSAR model using the random forest algorithm with 92.2% accuracy. Virtual screening results of > 10 million molecules obtained 2 716 hits compounds with a pIC₅₀ value of > 7.5. Additionally, molecular docking results of several potential hit compounds for DPP-4, DPP-8, and DPP-9 identified CH0002 as showing high inhibitory potential against DPP-4 and low inhibitory potential for DPP-8 and DPP-9 enzymes. These results demonstrated the effectiveness of this technique for identifying DPP-4-inhibitor hit compounds selective for DPP-4 and against DPP-8 and DPP-9 and suggest its potential efficacy for applications to discover hit compounds of other targets.     

Synthesis of Rottlerone Analogues and Evaluation of Their α-Glucosidase and DPP-4 Dual Inhibitory and Glucose Consumption-Promoting Activity

Our previous study found that desmethylxanthohumol (1) inhibited α-glucosidase in vitro. Recently, further investigations revealed that dehydrocyclodesmethylxanthohumol (2) and its dimer analogue rottlerone (3) exhibited more potent α-glucosidase inhibitory activity than 1. The aim of this study was to synthesize a series of rottlerone analogues and evaluate their α-glucosidase and DPP-4 dual inhibitory activity. The results showed that compounds 4d and 5d irreversibly and potently inhibited α-glucosidase (IC₅₀ = 0.22 and 0.12 μM) and moderately inhibited DPP-4 (IC₅₀ = 23.59 and 26.19 μM), respectively. In addition, compounds 4d and 5d significantly promoted glucose consumption, with the activity of 5d at 0.2 μM being comparable to that of metformin at a concentration of 1 mM.     

Association of （S）-Isoserine Derivatives and 2,2,4-Trimethyl-3-hydroxy-4- cyclohexenecarboxylate

IntroductionOptimization of leading structures is an importantsector in the study and exploitation of medicine, andthe association of 2,2,4-trimethyl-3-hydroxyl-cyclohex-4-enecarboxylic acid (1) and isoserine derivatives isone of the best methods for the …     

合成Exendin-4的体外人血浆稳定性研究

为了解决Ⅱ型糖尿病患者注射用药频繁的问题, 需要比Exendin-4更加稳定的GLP-1的激动剂, 本文的研究目的是找到Exendin-4较易水解的氨基酸位点, 为设计新的长效的Exendin-4模拟肽提供相关信息.     

4-芳基-6-芳氧甲基吗啉-3-酮衍生物的合成及其对A549肺癌细胞生长抑止活性的评价

A series of 4-aryl-6-aryloxymethylmorpholin-3-one derivatives were synthesized very efficiently from readily available starting compounds in two steps. Ring opening reactions of epoxides with aniline compounds on alumina gave corresponding β-aminoalcohols （3）. The resulting β-aminoalcohols were reacted with 2-chloroacetyl chloride to yield the desired 4-aryl-6-aryloxymethylmorpholin-3-one derivatives （5）. All compounds 5 were assayed for inhibitory activity against A549 lung cancer cell growth, and the inhibitory effect of the novel morpholin-3-ones on cell viability was dose-dependent.     

Structure-based virtual screening of dipeptidyl peptidase 4 inhibitors and their in vitro analysis

Type 2 diabetes mellitus (T2DM) is one of the most widely prevalent metabolic disorders with no cure to date thus remains the most challenging task in the current drug discovery. Therefore, the only strategy to control diabetes prevalence is to develop novel efficacious therapeutics. Dipeptidyl Peptidase 4 (DPP-4) inhibitors are currently used as anti-diabetic drugs for the inhibition of incretins. This study aims to construct the chemical feature based on pharmacophore models for dipeptidyl peptidase IV. The structure-based pharmacophore modeling has been employed to evaluate new inhibitors of DPP-4. A four-featured pharmacophore model was developed from crystal structure of DPP-4 enzyme with 4-(2-aminoethyl) benzenesulfonyl fluoride in its active site via pharmacophore constructing tool of Molecular Operating Environment (MOE) consisting F1 Hyd (hydrophobic region), F2 Hyd|Cat|Don (hydrophobic cationic and donor region), F3 Acc (acceptor region) and F4 Hyd (hydrophobic region). The generated pharmacophore model was used for virtual screening of in-house compound library (the available compounds which were used for initial screening to get the few compounds for the current studies). The resultant selected compounds, after virtual screening were further validated using in vitro assay. Furthermore, structure-activity relationship was carried out for the compounds possessing significant inhibition potential after docking studies. The binding free energy of analogs was evaluated via molecular mechanics generalized Born surface area (MM-GBSA) and Poisson-Boltzmann surface area (MM-PBSA) methods using AMBER 16 as a molecular dynamics (MD) simulation package. Based on potential findings, we report that selected candidates are more likely to be used as DPP-4 inhibitors or as starting leads for the development of novel and potent DPP-4 inhibitors.     

Synthesis of bi- and tetracatenar highly fluorinated compounds for grafting on silicone materials

A series of highly fluorinated compounds bearing two or four perfluoroalkyl (R_F) chains, with a flexible or rigid core have been synthesized. Radical additions, nucleophilic addition or condensation reactions were implemented for these synthesis, using perfluoroalkylated iodides and alcohols and various type of substrates: bis(allylic) derivatives, epichlorhydrin, diacid derivatives. All compounds contain an unsaturated moiety (vinyl, allyl or internal double bond) to be grafted on silicone materials by a catalyzed hydrosilylation reaction.     

Synthesis and thermal properties of diurethanes containing various mesogenic units

Abstract

Five homologous series of diurethanes containing mesogenic moieties were synthesized by addition reactions of ω-alkenols to aromatic diisocyanates. The thermal behaviour of the compounds was studied by differential scanning calorimetry and on the hot stage of a polarizing microscope. Thermotropic liquid crystal behaviour was found for the diurethanes having a central core of more than two aromatic rings. Smectic C mesophases were observed for the derivatives of 4,4″-p-terphenylene and nematic mesophases for the diurethanes containing a di(4-phenylene)terephthalate unit. The compounds of both series possess high transition temperatures and narrow mesomorphic ranges.     

Design and synthesis of novel diamide derivatives of glycine as antihyperglycemic agents

DPP-4 inhibition is one of the most extensively explored approaches for the management of type 2 diabetes (T2D). Most DPP-4 inhibitors in the market contain a proline mimetic active pharmacophore. Herein, we report the design, synthesis, and preliminary evaluation of a series of novel diamide derivatives of glycine, devoid of the proline mimic, for the treatment of T2D. As predicted from in silico studies, the diamide derivatives of glycine exhibited comparable DPP-4 inhibition with the standard as confirmed by the preliminary in vitro studies. Compound 6b was found to be the most potent (IC₅₀ 94.82 nM) DPP-4 inhibitor among all the molecules synthesized in the series.