基于抗血小板聚集的一系列β-丙氨酸衍生物的合成与活性研究

为了寻找新的抗血小板聚集药物,以川芎嗪、β-丙氨酸、阿魏酸及其类似物为起始原料,经过一系列反应,合成了6个川芎嗪芳酸醚β-丙氨酸类衍生物.所有目标化合物均未见文献报道,其结构经1HNMR、13CNMR、IR、MS得到确证.药理结果初步显示,目标化合物血小板抑制率分别为6.4%、27.4%、7.7%、14.8%、37.0...     

川芎嗪-丁苯酞衍生物的设计、合成及抗血小板聚集活性研究

以邻苯二甲酸酐和川芎嗪为原料,经自由基取代、正丁基锂亲核加成、对甲基苯磺酸催化脱水、Pd/C加氢还原、水解、酯化等反应合成了3个川芎嗪与丁苯酞拼合衍生物,其结构经1HNMR、13CNMR和HR-MS确证.其中(3,5,6-三甲基吡嗪-2-基)甲基-2-戊酰基苯甲酸酯对由腺苷二磷酸(ADP)诱导的血小板聚集活性抑制率IC50为0.26 mmol/L,优于母体化合物川芎嗪和丁苯酞,是具有良好开发前景的候选化合物.     

川芎嗪硫化氢供体衍生物的设计、合成及其抗血小板聚集活性研究

依据药物化学中的活性拼接和生物电子等排原理,以4-羟基苯乙酮和川芎嗪为原料,经取代、环化、氧化、酯化、醚化等反应,合成了3个川芎嗪硫化氢供体衍生物,其结构经~1HNMR、~(13)CNMR和HR-MS确证。并采用Born比浊法初步测试了衍生物的体外抗血小板凝集活性,结果表明4-(3-硫代-3H-1,2-二硫杂环戊烯-5-基)苯基-3,5,6-三甲基吡嗪-2-甲酸酯对二磷酸腺苷(ADP)诱导的体外血小板聚集的抑制率IC_(50)为1.16 mmol/L,优于阳性对照物川芎嗪、丁苯酞、依达拉奉和阿司匹林,是值得进一步研究的治疗心脑血管疾病的候选化合物。     

香豆素硝酸酯类衍生物的合成及抗血小板聚集活性

以间苯二酚与乙酰乙酸乙酯为原料制备4-甲基-7-羟基香豆素,利用其7位羟基与二溴烷烃反应得到4-甲基-7-溴烷氧基香豆素,再将其与硝酸银反应得到5个香豆素硝酸酯类衍生物。目标化合物经红外光谱、核磁共振氢谱、质谱表证。体外抗血小板聚集活性测试结果表明,化合物4-甲基-7-硝氧烷氧基香豆素(4a~4e)对二磷酸腺苷(ADP)所诱导的血小板聚集均具有较强的抑制活性,其IC_(50)值为0.012~0.046mmol,强于阳性对照药阿司匹林(IC_(50)值为0.052mmol)。     

丹皮酚曼尼希碱衍生物的合成及抗血小板聚集活性

以丹皮酚为起始原料,以体积分数为95%乙醇水溶液为溶剂,与多聚甲醛和有机胺经Mannich反应得到得到丹皮酚曼尼希碱衍生物2a～2e。目标化合物2a～2e经红外、核磁共振氢谱和高分辨质谱表证。体外抗血小板聚集活性测试结果表明,所得目标化合物2a～2e对二磷酸腺苷(ADP)和胶原(collagen)所诱导的血小板聚集均具有较强的抑制活性,且明显优于阳性对照药阿司匹林。     

丹皮酚硝氧烷基醚类衍生物的合成及抗血小板聚集活性

以丹皮酚为原料,利用其2位羟基与二溴烷烃反应得到中间体丹皮酚溴代烷基醚(2a～2e),再将化合物2a～2e与硝酸银反应得到丹皮酚硝氧烷基醚类衍生物3a～3e.化合物3a～3e的结构经红外、核磁共振氢谱和高分辨质谱表征.体外抗血小板聚集活性测试结果表明,化合物3a～3e对二磷酸腺苷所诱导的血小板聚集均具有较强的抑制活性,...     

香豆素-3-羧酸-烟酸前药的设计、合成及抗血小板聚集活性的研究

设计、合成香豆素-3-羧酸-烟酸前药并研究其抗血小板聚集活性,以发现活性更高的新型抗血小板聚集剂。利用拼合原理,以不同的连接桥将香豆素-3-羧酸和烟酸偶联,合成目标化合物。通过体外抗血小板聚集试验对目标化合物进行抗血小板聚集活性评价。设计、合成了5个新的目标化合物,其结构经ESI-MS、IR及1 H NMR确证。体外抗血小板聚集活性结果表明,目标化合物的抗血小板聚集活性均强于阳性对照药阿司匹林,其中化合物6a的活性最强,值得进一步研究。     

丹皮酚吗啉杂合物的合成及抗血小板聚集活性

以丹皮酚为起始原料,在碱性条件下丹皮酚的2-位酚羟基与二溴烷烃经Williamson反应得到中间体丹皮酚溴代烷基醚2a～2e,化合物2a～2e与吗啉经N-烷基化反应得到丹皮酚吗啉杂合物3a～3e。目标化合物3a～3e经过核磁共振氢谱(¹H NMR)、红外(IR)和高分辨质谱(HRMS)表征。体外抗血小板聚集活性测试结果表明,所得目标化合物3a～3e对二磷酸腺苷(ADP)所诱导的血小板聚集均具有较强的抑制活性,优于阳性对照药阿司匹林。     

4-色满酮曼尼希碱类化合物的合成及其抗血小板聚集活性

4-色满酮类化合物具有广泛的生物活性。为了考察4-色满酮类化合物的抗血小板聚集活性构效关系,笔者设计合成了10种4-色满酮Mannich碱类化合物,其组成和结构经熔点、红外光谱和核磁共振氢谱确证,其中6个(5d～5g,5i～5j)目标化合物均未见文献报道。采用Born's比浊法对目标化合物进行了抗血小板聚集活性的体外筛选,实验结果表明,目标化合物对二磷酸腺苷(ADP)诱导的家兔血小板聚集均具有显著的体外抑制活性。     

基于抗血小板聚集的新型吡考他胺类似物的合成及其活性研究

以吡考他胺为先导化合物,依据生物电子等排体原理,设计并合成了3个标题化合物,所有化合物均未见文献报道,其结构均经IR、1HNMR、13CNMR和MS确证。采用Bron比浊法测定了标题化合物对腺苷二磷酸(Adenosine diphosphate,ADP)及花生四烯酸(Arachidonic acid,AA)诱导的血小板聚集的抑制活性。初步药理结果显示,标题化合物对ADP诱导的血小板聚集均具有显著的抑制活性,其中4-甲氧基-N1,N3-二((3,5,6-三甲基吡嗪-2-基)甲基)间苯二甲酰胺和4-甲氧基-N1,N3-二((5-甲基吡嗪)-2-亚甲基)间苯二甲酰胺对AA诱导的血小板聚集也显示出较强的抑制活性。     

吗啉芳酸衍生物的合成

目的：合成吗啉芳酸衍生物并优化其合成工艺。方法：以芳酸酯为起始原料,经Williamson醚化、亲核取代反应和水解反应合成目标化合物。结果：所合成的目标化合物未见文献报道,其结构经IR1、H-NMR1、3C-NMR及MS得到确证。结论：所设计的合成技术简单易行,适合工业化生产。     

五元氮杂环阿魏酸衍生物的合成

目的：合成4个五元氮杂环阿魏酸衍生物。方法：以阿魏酸乙酯为起始原料,经Williamson醚化、亲核取代反应和水解反应,合成五元氮杂环阿魏酸衍生物。结果：所合成的目标化合物未见文献报道,目标化合物的结构经IR、1H-NMR、13C-NMR及MS确证。结论：所设计的合成技术简单易行。     

Inhibitory Mechanisms of Lusianthridin on Human Platelet Aggregation

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum. Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC₅₀ of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC₅₀ value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration (p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.     

扁桃酸-噻二唑酰胺衍生物的合成及明胶酶抑制活性

为了寻找选择性高、亲和性强的新型明胶酶抑制剂类抗肿瘤药物,以(R)-(-)-扁桃酸与合成中间体5-取代-1,3,4-噻二唑-2-胺为原料,基于三甲基氯硅烷的羟基保护作用,经酰氯化、酰胺化等反应合成出12个扁桃酸-噻二唑酰胺衍生物,并对明胶酶(MMP-2,MMP-9)进行初步体外抑酶活性评价。结果显示,浓度为10μmol/L时,(2R)-N-[2-[5-(4-硝基苯基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺对MMP-2和MMP-9同时具有最强的抑制活性,抑制率分别为80.17%和70.16%,化合物(2R)-N-[2-[5-(3-硝基苯基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺、(2R)-N-[2-[5-苯甲基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺和(2R)-N-[2-[5-(4-氯苯氧甲基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺对MMP-2有较强的抑制活性,化合物(2R)-N-[2-[5-苯甲基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺、(2R)-N-[2-[5-苯乙基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺和(2R)-N-[2-[5-(2,4-二氯苯氧甲基)-1,3,4-噻二唑]]-2-羟基-苯乙酰胺对MMP-9有中等强度的抑制活性。     

6-烃氧基-2-烷硫基腺苷化合物的合成及抗血小板凝聚活性

以鸟嘌呤核苷(Ⅰ)为原料,经羟基保护得到2',3',5'-三-O-乙酰基鸟嘌呤核苷(Ⅱ),Ⅱ与三氯氧磷反应得到2-氨基-6-氯-9-(2',3',5'-三-O-乙酰基-β-D-呋喃核糖基)嘌呤(Ⅲ),Ⅲ再进行重氮-烷硫化反应,生成2-烷硫基-6-氯-9-(2',3',5'-三-O-乙酰基-β-D-呋喃核糖基)嘌呤(Ⅳ),Ⅳ与醇进行亲核取代反应同时脱去糖环保护得到8个6-烃氧基-2-烷硫基嘌呤腺苷化合物(Ⅴ)。化合物的结构经1HNMR、13CNMR、IR和HRMS表征,同时对合成的目标化合物进行了体外抗血小板凝聚活性测试。结果表明,在测试浓度为10μmol/L时,6-(2-呋喃甲基)氧基-2-丙硫基腺苷具有较高的抗血小板凝聚活性。     

Design and Synthesis of Acridine-Triazole and Acridine-Thiadiazole Derivatives and Their Inhibitory Effect against Cancer Cells

We report herein the design and synthesis of a series of novel acridine-triazole and acridine-thiadiazole derivatives. The newly synthesized compounds and the key intermediates were all evaluated for their antitumor activities against human foreskin fibroblasts (HFF), human gastric cancer cells-803 (MGC-803), hepatocellular carcinoma bel-7404 (BEL-7404), large cell lung cancer cells (NCI-H460), and bladder cancer cells (T24). Most of the compounds exhibited high levels of antitumor activity against MGC-803 and T24 but low toxicity against human normal liver cells (LO2), and their effect was even better than the commercial anticancer drugs, 5-fluorouracil (5-FU) and cis-platinum. Further, pharmacological mechanisms such as topo I, cell cycle, cell apoptosis, and neovascularization were all evaluated. Only a few compounds exhibited potent topo I inhibitory activity at 100 μM. In addition, the most active compounds with an IC₅₀ value of 5.52–8.93 μM were chosen, and they could induce cell apoptosis in the G2 stage of MGC-803 or mainly arrest T24 cells in the S stage. To our delight, most of the compounds exhibited lower zebrafish cytotoxicity but could strongly inhibit the formation of zebrafish sub-intestinal veins, indicating a potential for clinical application.     

Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation

Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings support a role for acetylation signaling in coordinating signaling systems that drive platelet cytoskeletal changes and aggregation. Therefore, we investigated the impact of ACC inhibition on tubulin acetylation and platelet functions. Human platelets were incubated 2 h with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. We have herein demonstrated that CP640.186 treatment does not affect overall platelet lipid content, yet it is associated with increased tubulin acetylation levels, both at the basal state and after thrombin stimulation. This resulted in impaired platelet aggregation. Similar results were obtained using human platelets that were pretreated with tubacin, an inhibitor of tubulin deacetylase HDAC6. In addition, both ACC and HDAC6 inhibitions block key platelet cytoskeleton signaling events, including Rac1 GTPase activation and the phosphorylation of its downstream effector, p21-activated kinase 2 (PAK2). However, neither CP640.186 nor tubacin affects thrombin-induced actin cytoskeleton remodeling, while ACC inhibition results in decreased thrombin-induced reactive oxygen species (ROS) production and extracellular signal-regulated kinase (ERK) phosphorylation. We conclude that when using washed human platelets, ACC inhibition limits tubulin deacetylation upon thrombin stimulation, which in turn impairs platelet aggregation. The mechanism involves a downregulation of the Rac1/PAK2 pathway, being independent of actin cytoskeleton.     

没食子酸酯合成方法改进及其抗血小板聚集作用

没食子酸乙酯、丙酯、丁酯及十二烷醇酯的合成,用对甲苯磺酸替代浓硫酸作催化剂,采用梯度升温法进行合成。乙酯和丙酯的合成还摒弃了带水剂。最佳的合成条件为：丙酯和乙酯：酸、醇、催化剂的摩尔比为０．０８２５∶０．９３４∶０．００５２４,反应温度为１２０℃,反应时间４ｈ,收率９４２％和８５４％。丁酯：酸、醇、催化剂的摩尔比为０．０５２２∶０．８７４∶０．００３９４,反应温度为１１５～１２０℃,反应时间５ｈ,收率８６８％。十二烷醇酯：以１,４ 二氧六环作溶剂,４Ａ分子筛作吸水剂,酸、醇、催化剂的摩尔比为０．０７５∶０．０９１∶０．０１２,反应温度为１２４℃,反应时间为１４ｈ,收率９３７％。异丙酯：采用干燥氯化氢作催化剂,没食子酸与异丙醇的摩尔比为０１４７∶１３７,加热回流８ｈ,收率８８１％。十二烷醇酯的抗血小板聚集性能最好。     

卟啉及其衍生物的合成研究进展

卟啉及其金属配合物由于其结构的易修饰性和性质的可调控性成为常用的超分子骨架。从卟啉环合方法和卟啉取代基修饰两个方面综述了卟啉及其衍生物的合成研究进展;以卟啉经典合成方法为基础,介绍了各类复杂结构卟啉的合成条件及适用范围。