新型拟天然芪类拓扑异构酶Ⅰ抑制剂的设计与合成

为了寻找新型抗肿瘤药物先导,设计合成了23个含噻唑环的天然芪类似物,其结构均经NMR和ESI-HRMS表征确证.通过Top1-介导的松散实验筛选了目标化合物的拓扑异构酶I(Top1)抑制活性,其中(E)-5-溴-2-(2-氯苯乙烯基)-4-对氟苯基噻唑(6k)显示出了良好的Top1抑制活性.同时通过分子对接研究其构效关...     

拟天然联三苯类拓扑异构酶Ⅱα抑制剂的设计合成（英文）

设计合成了系列新的拟天然联三苯类衍生物,并对其生物活性进行了分析.其中4-氨基-(1,1':4,1'-三联苯)-3-二醇(17)具有最强的MDA-MB-435细胞增殖抑制活性, IC_(50)为(0.20±1.12)μmol/L,显著优于我们之前报道的同类化合物X1和X2.DNA松弛实验结果表明,化合物17具有较强的DNA拓扑异构酶Ⅱα的抑制活性,但是对DNA拓扑异构酶Ⅰ活性无明显抑制作用.分子模拟对接分析结果进一步验证, C环上的氮取代基对化合物17选择性抑制DNA拓扑异构酶IIα活性有重要作用,为设计合成新的联三苯类高效拓扑异构酶Ⅱα抑制剂提供了新思路.     

新型拟天然芪类拓扑异构酶Ⅰ抑制剂的设计与合成（英文）

为了寻找新型抗肿瘤药物先导,设计合成了23个含噻唑环的天然芪类似物,其结构均经NMR和ESI-HRMS表征确证.通过Top1-介导的松散实验筛选了目标化合物的拓扑异构酶Ⅰ(Top1)抑制活性,其中(E)-5-溴-2-(2-氯苯乙烯基)-4-对氟苯基噻唑(6k)显示出了良好的Top1抑制活性.同时通过分子对接研究其构效关系,结果表明化合物的Top1抑制活性与分子对接研究之间具有良好的相关性.此外,采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐(MTT)法测定了化合物对人乳腺癌细胞(MCF-7)和人结肠癌细胞(HCT116)的体外抗肿瘤活性,结果表明(E)-5-溴-4-对氟苯基-2-(4-三氟甲基苯乙烯基)噻唑(6e)、(E)-5-溴-2-(2-氯苯乙烯基)-4-对氟苯基噻唑(6k)和(E)-5-溴-2-(4-氯苯乙烯基)-4-对氟苯基噻唑(6l)在低摩尔浓度下表现出较高的细胞毒活性.     

新型喹唑啉类酪氨酸激酶化学抑制剂的设计与合成

以6-氨基藜芦酸和醋酸甲脒为起始原料,合成了一系列4-位具有不同芳胺基团,6,7-位引入不同取代基的新型喹唑啉类酪氨酸激酶化学抑制剂,其结构经1H NMR表征.     

新型光系统II抑制剂的设计、合成和生物活性测定

根据药效团模型,合理设计并合成了新型光系统II(PSII)抑制剂化合物,进行 了元素分析和红外、紫外及核磁数据表征。希尔反应测试表明,亿合成的化合物均 具有抑制光系统II电子传递功能的生物活性,有的化合物活性较高,为新型PSII除 草剂的开发显示了广阔的应用前景。     

新型光系统II抑制剂的设计、合成和生物活性测定

根据药效团模型，合理设计并合成了新型光系统II(PSII)抑制剂化合物，进行 了元素分析和红外、紫外及核磁数据表征。希尔反应测试表明，亿合成的化合物均 具有抑制光系统II电子传递功能的生物活性，有的化合物活性较高，为新型PSII除 草剂的开发显示了广阔的应用前景。     

3-芳基-7-羟基喹啉类拓扑异构酶Ⅱα抑制剂的合成及抗肿瘤活性研究

人脱氧核糖核酸(DNA)拓扑异构酶Ⅱα(topoisomerase Ⅱα, Topo Ⅱα)是重要的抗肿瘤药物靶标之一.为发现高效、低毒的Topo Ⅱα抑制剂,通过对先导化合物6-(3,4-二羟基苯基)萘酚(CS1)进行骨架跃迁,设计合成了21个3-芳基-7-羟基喹啉衍生物.采用DNA松弛实验评价体外Topo Ⅱα抑制活性,结果显示大部分化合物对Topo Ⅱα活性有抑制作用;采用人三阴乳腺癌MDA-MB-231细胞和人宫颈癌HeLa细胞生长抑制实验体外评价抗肿瘤活性,结果表明3-(2,4-二甲氧基苯基)-7-羟基喹啉(4j)对HeLa细胞有明显毒性(IC_(50)=0.8μmol·L~(-1)), 3-(4-羟基苯基)-7-羟基喹啉(4e)对MDA-MB-231(IC_(50)=1.1μmol·L~(-1))和HeLa(IC_(50)=4.2μmol·L~(-1))细胞均有明显毒性,阳性对照CS1对MDA-MB-231和HeLa细胞的IC_(50)值分别为3.8和2.5μmol·L~(-1).研究结果为设计合成新的喹啉类高效拓扑异构酶Ⅱα抑制剂提供了新思路.     

新型喹唑啉类PDE7抑制剂类似物的合成

以邻氨基苯甲酸为原料,经溴代和环合反应合成了4个新型喹唑啉类PDE7抑制剂类似物,其结构经1H NMR和ESI-MS表征。     

6-取代芳基-2-甲氧基喹啉类拓扑异构酶Ⅱα抑制剂的合成及抗肿瘤活性研究

人DNA拓扑异构酶Ⅱα(topoisomerase Ⅱα, Topo Ⅱα)是重要的抗肿瘤药物研究靶标之一.前期研究发现对联三苯类化合物对TopoⅡα有抑制作用,并且抑制人乳腺导管癌细胞增殖.本研究通过对联三苯类化合物的骨架跃迁,设计合成了19个6-取代芳基-2-甲氧基喹啉类衍生物3a～3s,包括取代苯基、氮硫杂环和萘环等.体外人三阴乳腺癌MDA-MB-231细胞株生长抑制实验和Topo Ⅱα抑制实验结果表明, 6-(4-羟甲基苯基)-2-甲氧基喹啉(3b)有明显细胞毒性和Topo Ⅱα抑制活性(IC_(50)=9.9μmol·L~(-1)).研究结果为研发新型Topo Ⅱα抑制剂提供了新方向,对肿瘤的预防和治疗具有重要意义.     

新型苯甲酰胺类HDAC抑制剂的合成及其抗肿瘤活性

以MS-275为先导化合物,设计并合成了7个新型苯甲酰胺类化合物（6a~6c, 14a, 14b, 15a和18）,其结构经¹H NMR和ESI-MS表征。采用MTT法测定了6a~6c, 14a, 14b, 15a和18对人急性白血病细胞(HL60)和人乳腺癌细胞(MCF-7)的体外抗肿瘤细胞增殖活性。结果表明：N-(2-氨基苯)-3-［4-(吡啶-3-基)嘧啶-2-氨基］己酰胺（6a）, N-(2-氨基苯)-4-【3-{4-［(二乙胺基)甲基］苯基}丙烯酰】苯甲酰胺（14a）和N-(2-氨基苯)-4-［3-(吡啶-3-基)丙烯酰］丙酰胺(18）的抑制活性较好,其GI₅₀依次为5.72 μmol·L^-1, 6.91 μmol·L^-1, 7.11 μmol·L^-1和3.46 μmol·L^-1, 4.12 μmol·L^-1, 3.97 μmol·L^-1,优于MS-275(7.88 μmol·L^-1和4.49 μmol·L^-1)。     

Design,Synthesis and Cytotoxicity of Thiazole-Based Stilbene Analogs as Novel DNA Topoisomerase IB Inhibitors

A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 with Top1–DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC₅₀ values at micromolar concentrations. Compounds 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) exhibited the most potent cytotoxicity with IC₅₀ values of 0.78 and 0.62 μM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure–activity relationships of thiazole-based stilbene analogs was also discussed.     

纺锤体驱动蛋白抑制剂的设计、合成与生物活性研究

纺锤体驱动蛋白(kinesin spindle protein, KSP/Eg5)作为潜在的肿瘤治疗靶点, 使发现KSP抑制剂成为热点. 设计并合成了4-氧基-β-四氢咔啉衍生物作为新型的KSP抑制剂, 并测定了其对KSP的抑制活性, 均优于阳性对照物. 其中化合物9c抑制KSP的IC50＝0.065 μmol•L－1, 优于阳性对照物Monastro l100多倍. 生物活性研究表明为抗肿瘤药物提供了新结构类型的候选化合物.     

Synthesis of Novel Monomeric Dyes with Anthraquinone Residue

Two novel polymerizable dyes with anthraquinone residue have been prepared, and their structures were characterized by FTIR, ^1HNMR and EA.     

新型吡啶类c-Met激酶抑制剂的设计、合成及抗肿瘤活性

以BMS-777607和E7050为先导化合物,设计并合成了11个新型的吡啶类c-Met激酶抑制剂（9a~9f和10a~10e）,其结构经¹H NMR和MS(ESI)表征。采用MTT法测定了9a~9f和10a~10e对人胃癌细胞株(NCI-N87和GTL-16)的体外抗肿瘤细胞增殖活性。结果表明：9a, 9d和10a对GTL-16的抑制活性较好,其IC₅₀分别为0.60 μmol·L^-1, 1.36 μmol·L^-1和0.93 μmol·L^-1,优于BMS-777607（2.50 μmol·L^-1）。     

新型5-HT重摄取抑制剂的设计、合成及活性评价

在对已知各种结构类型的5-HT重摄取抑制剂分子结构全面分析的基础上, 建立了SSRIs药效团模型. 基于该模型应用UNITY程序对NCI-3D和Maybridge-3D数据库进行三维结构的限制性查询, 在获得的命中结构的信息指导下, 设计合成了3种全新结构类型的化合物, 并完成了初步的药理活性评价. 这些化合物均显示出不同程度的5-HT重摄取抑制活性, 其中5个化合物显示高抑制活性. 哌嗪取代的二苯脒类化合物的结构新颖, 较好地符合5-HT重摄取抑制剂药效团模型, 与SSRIs类化合物三维定量构效关系研究得到的CoMFA模型有较好的适配性.     

基于药效团模型设计合成新型ALS抑制剂

以ALS抑制剂药效团模型为基础建立了提问结构,将药效团模型中的生物结构信息输入到多种小分子三维结构数据库(NCI-3D和ACD-3D数据库)中,分别搜寻出100多个符合特征结构信息的全新结构候选化合物.以这些命中结构的分子特征信息为基础设计合成了一系列新型的ALS抑制剂,初步生物活性测试结果表明,预期有生物活性的化合物显示出一定的ALS酶抑制剂活性.     

新型双苯甲酰基脲类化合物的合成

从原料百菌清出发,经过氟交换、氨解、水解、脱羧和酰化反应,合成得到12个新型双苯甲酰基脲类几丁质抑制剂衍生物,总收率超过30％-50％。     

含蒽醌结构新型共聚酯染料的合成及性能

以溶液聚合法合成了以１,５－二－β－羟乙醚基蒽醌为染料单体的新型共取酯染料,通过紫外－可见、核磁共振、热重等方法对聚合物性能进行表征,将其作为色母在毛细管流变仪上对聚酯纤维进行共混染色,并测定其光宾度。     

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

A novel class of nonpeptidic, active, and selective thrombin inhibitors has resulted from X‐ray‐structure‐based design and subsequent improvement of the initial lead molecules. These inhibitors possess a bi‐ or tricyclic central core structure with attached side chains to reach the three binding pockets (selectivity S1 pocket, distal D pocket, and proximal P pocket) present in the active site of the enzyme. The key step in the preparation of these compounds is the 1,3‐dipolar cycloaddition between an azomethine ylide, prepared in situ by the decarboxylative method from an aromatic aldehyde and an α‐amino acid, with an N‐substituted maleimide (e.g., see Schemes 1 and 2). All potent inhibitors contain an amidinium residue in the side chain for incorporation into the S1 pocket, which was introduced in the last step of the synthesis by a Pinner reaction. The compounds were tested in biological assays for activity against thrombin and the related serine protease trypsin. The first‐generation lead compounds (±)‐ 11 and (±)‐ 19 (Scheme 1) with a bicyclic central scaffold showed K_i values for thrombin inhibition of 18 μM and 0.67 μM , respectively. Conformationally more restricted second‐generation analogs (Scheme 2) were more active ((±)‐ 22i : K_i=90 nM (Table 1)); yet the selectivity for thrombin over trypsin remained weak. In the third‐generation compounds, a small lipophilic side chain for incorporation into the hydrophobic P pocket was introduced (Schemes 7 and 8). Since this pocket is present in thrombin but not in trypsin, an increase in binding affinity was accompanied by an increase in selectivity for thrombin over trypsin. The most selective inhibitor (K_i=13 nM , 760‐fold selectivity for thrombin over trypsin; Table 2) was (±)‐ 1 with an i‐Pr group for incorporation into the P pocket. Optical resolution of (±)‐ 1 (Scheme 9) provided (+)‐ 1 with a K_i value of 7 nM and a 740‐fold selectivity, whereas (−)‐ 1 was 800‐fold less active (K_i=5.6 μM , 21‐fold selectivity). The absolute configuration of the stronger‐binding enantiomer was assigned based on the X‐ray crystal structure of the complex formed between thrombin and this inhibitor. Compound (+)‐ 1 mimics the natural thrombin substrate, fibrinogen, which binds to the enzyme with the Ph group of a phenylalanine (piperonyl in (+)‐ 1 ) in the distal D pocket, with the i‐Pr group of a valine (i‐Pr in (+)‐ 1 ) in the proximal P pocket, and with a guanidinium side chain of an arginine residue (phenylamidinium group in (+)‐ 1 ) in the selectivity S1 pocket of thrombin. A series of analogs of (±)‐ 1 with the phenylamidinium group replaced by aromatic and aliphatic rings bearing OH or NH₂ groups (Schemes 10 – 14) were not effectively bound by thrombin. A number of X‐ray crystal‐structure analyses of free inhibitors confirmed the high degree of preorganization of these compounds in the unbound state. Since all inhibitors prefer similar modes of association with thrombin, detailed information on the strength of individual intermolecular bonding interactions and their incremental contribution to the overall free energy of complexation was generated in correlative binding and X‐ray studies. The present study demonstrates that defined mutations in highly preorganized inhibitors provide an attractive alternative to site‐directed mutagenesis in exploring molecular‐recognition phenomena at enzyme active sites.