奥拉西坦衍生物的设计、合成及抗血小板聚集活性研究

本文采用拼合策略,设计、合成了7个新型奥拉西坦衍生物。其中,化合物4a～4f由奥拉西坦与苯丙烯酸片段拼合得到; 4g则由奥拉西坦、吲哚布芬拼合得到。采用Bron比浊法测定目标化合物对花生四烯酸及二磷酸腺苷诱导的血小板聚集的抑制活性。结果表明,该系列化合物具有一定的抗血小板聚集活性,其中化合物4f的抗血小板聚集活性与阳性对照吲哚布芬相当。     

Synthesis,anti-platelet aggregation activity evaluation and structure–activity relationships of a series of novel purine derivatives

This article described how further extensive variation of the substituents on the purine scaffold of adenosine triphosphate (ATP), and the human anti-platelet aggregation activities were modified in order to find exploitation of the structure–activity relationships (SAR). A series of novel designed 6-alkylamino-2-alkylthio-9-hydroxyalkyl(carbalkoxy) purine derivatives were synthesized via a modification procedure, and the human anti-platelet aggregation activities were evaluated. The SAR of these compounds were analyzed in detail, and the results of the structural requirements of the substituents to improve potency may provide a basis for the development of potent P2Y₁₂ antagonists.     

Synthesis and anti-platelet, anti-inflammatory and anti-allergic activities of methoxyisoflavanquinone and related compounds

In a continuation of our search for novel anti-platelet agents, isoflavone quinone and isoflavanquinone were selected as lead compounds and the synthesis of their methoxy derivatives was carried out. Among them, the 4'- and 7-methoxy derivatives were successfully prepared, whereas the attempt to obtain 3'-methoxy derivatives resulted in their isomers, 3'-methoxyflavone quinone and 3'-methoxyflavanquinone, instead. After screening for their anti-platelet, anti-inflammatory and anti-allergic activities, a preliminary structure-activity relationship was established. Compounds 6c, 7a-c, 8c and 9a-c were found to exhibit significant activities. In particular, compound 7c demonstrated very potent anti-platelet, anti-inflammatory and anti-allergic activities and was then recommended for further pharmacological investigation.     

新型三唑并[4,5-d]嘧啶类化合物的合成及其抗血小板聚集活性

以2-丙硫基-4,6-二氯-5-氨基嘧啶为原料,与伯胺类化合物(1)经取代反应制得氨基嘧啶类化合物(2);2经重氮化反应制得三氮唑类化合物(3);3与胺类化合物经亲核取代反应和水解反应合成了26个新型的三唑并[4,5-d]嘧啶类化合物(6a~6z),其结构经1H NMR和ESI-MS表征。大鼠体内抗血小板聚集模型测试结果表明:26个化合物均具有一定的抗血小板聚集活性,其中,6d,6i和6l的抗血小板聚集活性较强,抑制率分别为61.9%,69.3%和71.2%。     

Facile synthesis of (+/-)-paeonilide

(+/-)-Paeonilide, a novel monoterpenoid metabolite from the roots of Paeonia delavayi showing anti-platelet activating factor activity, is convergently synthesized in five steps with 59% overall yield. The application of benzoyl peroxide-promoted radical addition of unsaturated ester to aldehyde and subsequent topologically favored cyclization greatly simplified the synthesis.     

Bio-click chemistry: enzymatic functionalization of PEGylated capsules for targeting applications

All sorted: The enzyme Sortase?A was used to catalyze functionalization of PEGylated capsules with an activation-specific anti-platelet single-chain antibody (scFv). This enzymatic method allows fast, covalent, and site-directed functionalization of delivery vehicles under mild conditions. Activation-specific anti-platelet scFv-coated PEGylated capsules exhibited a high level of selective binding to thrombi, thus suggesting their potential for thrombosis therapy.     

Polycyclic N-hetero compounds. XXXVII. A convenient synthesis and evaluation of anti-platelet aggregation activity of 1,2,4,5-tetrahydro[1]- benzothiepino[4,5-e]imidazo[1,2-c]pyrimidine and its related compounds

A simple and highly efficient methodology for the synthesis of 1,2,4,5-tetrahydro[1]benzothiepino[4,5-e]-imidazo[1,2-c]pyrimidine ( XI ) having a novel ring system via 4-substituted 5,6-dihydro[1]benzothiepino-[5,4-d]pyrimidines VII-X is described. The anti-platelet aggregation activity for it and its related compounds against collagen-induced aggregation of rabbit blood platelets in vitro was found.     

基于化学指纹图谱和抗血小板聚集效价的丹参质量评价

通过化学分析和生物活性评价考察丹参药材的品质差异,探讨丹参抗血小板聚集生物活性的主要贡献成分.采用高效液相色谱(HPLC)技术建立丹参药材HPLC指纹图谱,以抗血小板聚集相对效价作为指标,评价不同产地不同批次丹参药材的品质差异,构建基于化学表征及生物效价测定的评价模式.结果表明,不同批次丹参药材的HPLC指纹图谱相似度很高(相似度0.930~0.998),而其抗血小板聚集相对效价相差10倍,提示化学指纹图谱难以反映丹参的活性和质量差异.通过化学指纹图谱与抗血小板聚集生物效价进行谱效相关分析,筛选出与生物活性相关系数大于0.5的6个色谱峰:二氢丹参酮Ⅰ、隐丹参酮、丹参酮Ⅰ、丹参酮ⅡA及2个未知化合物.对上述4种已知化合物单体进行活性验证发现,隐丹参酮的抗血小板聚集活性最强,而其它3种丹参酮类化合物几乎没有体外抗血小板聚集活性.进一步比较丹参中高含量成分丹酚酸B与低含量成分隐丹参酮的活性贡献,结果表明,两者的活性贡献基本相当,说明隐丹参酮是丹参中低含量高活性成分,对评价丹参质量具有重要贡献度.     

Screening of anti-platelet aggregation agents from Panax notoginseng using human platelet extraction and HPLC-DAD-ESI-MS/MS

Root of Panax notoginseng (Sanqi in Chinese) is a highly valued and commonly used Chinese medicine. It has been widely used for treatment of cardio- and cerebro-vascular diseases. In this study, a method involving human platelet extraction and HPLC-DAD-ESI-MS/MS was developed for screening potential anti-platelet aggregation agents in Sanqi. Five compounds which could interact with human platelets were found, and four were identified as adenosine, guanosine, ginsenoside Rh1, and ginsenoside F1, respectively. The effects on rabbit platelet aggregation induced by arachidonic acid, adenosine diphosphate, and thrombin were also investigated in vitro. The results showed that the nucleosides adenosine and guanosine mainly contributed to the anti-platelet aggregation of Sanqi. The data suggest that human platelet extraction combined with HPLC-DAD-ESI-MS/MS is a useful method for screening anti-platelet aggregation agents from Chinese medicines.     

Synthesis and biological evaluation of n-butylphthalide derivatives as anti-platelet aggregation agents

New analogues of n-butylphthalide (NBP) bearing various lengths of alkyl and different substitution at the two-position of phthalide were designed and synthesised. Preliminary evaluation and prediction of ACD LogP software indicate that the derivatives display significant improvement in water solubility than NBP does. Further biological analysis showed that NBP analogues specifically inhibit platelet aggregation induced by arachidonic acid but have no effect on that induced by adenosine 5-diphosphate. Especially compounds 1 and 3 were stronger than classical anti-platelet drug, aspirin, and equal potent with NBP, respectively. These findings provide an alternative approach to the development of NBP analogues with anti-platelet aggregation activity with good water solubility for the intervention of ischemic stroke.     

Novel synthesis approach and antiplatelet activity evaluation of 6-alkylamino-2,4-dialkyl(aryl)thiopyrimidines

A new and efficient procedure has been designed for the preparation of 6-alkylamino-2,4-dialkyl(aryl)thiopyrimidines. The first alkylthio group was introduced into the pyrimidine ring by S-alkylation. The introduction of the second one was successfully achieved using the diazotization-alkylthionation method to afford 2,4-dialkyl(aryl)thio-6-chloropyrimidines. Subsequent nucleophilic displacement by the corresponding amines conveniently gave a series of the target compounds. Thus, the two same or different alkylthio groups were easily introduced into the pyrimidine ring through the two different approaches. The human anti-platelet aggregation activity of the newly synthesized compounds is also described.     

Anti-Platelet Aggregation and Vasorelaxing Effects of the Constituents of the Rhizomes of<em> Zingiber officinale</em>

In the present study, the chemical investigation of the bioactive fractions of the rhizomes of Zingiber officinale has resulted in the identification of twenty-nine compounds including one new compound, O-methyldehydrogingerol (1). Some of the isolates were subjected into the evaluation of their antiplatelet aggregation and vasorelaxing bioactivities. Among the tested compounds, [6]-gingerol (13) and [6]-shogaol (17) exhibited potent anti-platelet aggregation bioactivity. In addition, [10]-gingerol (15) inhibited the Ca²⁺-dependent contractions in high K⁺ medium. According to the results in the present research, the bioactivity of ginger could be related to the anti-platelet aggregation and vasorelaxing mechanism.     

肉桂酰酪胺类似物的合成与抗血小板聚集评价

为了探究肉桂酰酪胺的苯环上甲氧基取代、酪胺上羟基和酰胺上胺基被甲基化对衍生物抗血小板聚集活性的影响,以8种苯甲醛衍生物为原料,经过缩合反应及甲基化等反应制得肉桂酰酪胺类似物,经核磁共振波谱仪(NMR)、质谱(MS)、单晶衍射等技术手段表征了目标化合物结构。 基于变温核磁,探讨了化合物4a~4h中旋转异构及酰胺C-N键双键性质对氢核磁谱的影响。 采用Born比浊法对目标化合物进行活性筛选,9个类似物的活性均强于柄果花椒酰胺,特别是化合物2c、4c、4f在200 μmol/L时显示出强的抑制率,分别为50.03%、60.87%、53.33%。 该类化合物的构效关系是4位甲氧基取代对化合物的抗ADP(二磷酸腺苷)诱导血小板聚集活性最为有利,甲基化B环中的羟基和结构中的酰胺氮原子时,在某种程度上可增强化合物活性。     

Structure and function of annexin V-decorsin fusion

Decorsin is an antagonist of fibrinogen receptor on platelets and Annexin V is able to recognize stimulated platelets. Two recombinant proteins, Annexin V plus Decorsin (AnnV-D39) and Annexin V plus the C terminal 27 amino acids variant of Decorsin (AnnV-D27), were constructed, expressed, and purified. Platelet Aggregation assay results appear that AnnV-D39 shows good anti-platelet aggregation activity, but AnnV-D27 no such activities in any platelet aggregation assay test. And computational simulations reveal that AnnV-D39 showed good anti-platelet aggregation activity as a new antagonist of fibrinogen receptor, while Annv-D27 needs re-modification. Despite the AnnV_D39 fusion is more than decorsin, the former maintains the binding sites of decorsin interacton with its receptor, which contains Asp10, Arg28-Asp33, and Tyr37-Glu39. And the addition of Annexin V could not influence the interaction between its decorsin part with its receptor GPIIb–IIIa due to the linkage peptide (GGGGSGGGGS). Although the AnnV_D27 fusion is similar to the AnnV_D39 fusion, there are differences between them, where the former is in shortage of the linkage peptide and the N-terminal segment of decorsin whose one residue (Asp10) contribution to its interaction with GPIIb–IIIa. Meanwhile, these complex models suggest that decorsin plays a role in antiplatelet aggregation not only by its RGD motif interaction with its GPIIb–IIIa receptor, but also by other residues, especially Asp10 of its N-terminal segment and Tyr37-Glu39 of its C-terminal segment. On the other hand, the linkage peptide acts as avoidance of influence and blockage between domains of fusion. This is the cause that AnnV-D39 shows good anti-platelet aggregation activity.     

Three novel quassinoids, javanicolides A and B, and javanicoside A, from seeds of Brucea javanica

Two novel quassinoids, javanicolides A and B, and one novel quassinoid glucoside, javanicoside A were isolated from the seeds of Brucea javanica Merr. (Simaroubaceae), along with four known quassinoids, yadanziolides A and D, and bruceins D and E, and two known quassinoid glucosides, yadanziosides D and L. Their structures were elucidated by the analysis of spectral data and chemical evidence.     

Sensitive determination of free and plasma protein-bound dipyridamole by high-performance liquid chromatography

For many years dipyridamole (DP) has been used in the treatment of hypertension as a vasodilator, but recently it has been recognised as an anti-platelet aggregation agent and to potentiate anti-metabolite activity. A rapid and sensitive (20 nM) procedure for the determination of free and protein-bound DP in plasma, using reversed-phase high-performance liquid chromatography on an Ultrasphere XL ODS (3 microns) column (70 mm x 4.6 mm I.D.) with ultraviolet detection (280 nm), is reported. Free and bound DP were separated using ultrafiltration. Concentrations of DP between 0.1 and 10 microM were measured in plasma with a relative standard deviation of less than 9.6%. The subsequent determination of DP levels in patients orally administered 450 mg per day showed that DP binding to plasma protein is higher than 90%.     

Anti-platelet aggregation triterpene saponins from the galls of Sapindus mukorossi

Bioassay-directed fractionation of an ethanolic extract of the galls of Sapindus mukorossi has resulted in the isolation of two new tirucallane-type triterpenoid saponins, sapinmusaponins Q (1) and R (2), along with three known oleanane-type triterpenoid saponins (3-5). Their structures were elucidated on the basis of spectroscopic analysis and chemical hydrolysis. Biological evaluation showed that both sapinmusaponins Q and R demonstrated more potent anti-platelet aggregation activity than aspirin.     

GRGDS修饰D,L-丙交酯-β-苹果酸共聚物的生物相容性研究

聚(D,L-丙交酯-β-苹果酸)(P-COOH)进行改性制得GRGDS修饰聚合物(P-GS5),利用红外光谱、元素分析和X射线光电子能谱确定了材料的结构和组成.通过内皮细胞粘附实验发现P-GS5可明显提高内皮细胞粘附(PDLLA,45%;P-GS5,109%),改善材料的细胞亲和性;同时血小板粘附实验结果也表明P-GS5可有效抑制血小板粘附(PDLLA,47%;P-GS5,18%),降低血栓形成的几率.     

Chemical profiling and anticoagulant activity of Ginkgo Biloba leaves under the influence of harvesting time

Gingko biloba, family Gink, is used as a source of food and in traditional medicine for treatment of cough and promoting blood circulation, etc. The aim of the present work is to determine the chemical variation of G. biloba leaves collected from different harvesting time and in vitro anti-platelet aggregation effects, respectively. Methanol extract of G. biloba leaves was subjected to ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry analysis and triple quadrupole mass spectrometry. The anti-platelet aggregation effects induced by platelet-activating factor (PAF) and adenosine diphosphate (ADP) was measured by Born’s method. UHPLC-QTOF-MS analysis confirmed the presence of flavonoids, phenolic acid and terpene lactones in different sample. Partial least square discriminant analysis based on chemical profiling conducted to differentiate the samples according to their harvest time. All samples found highly effective against PAF-induced platelet aggregation with IC₅₀ of 98.87?μg/mL (summer sample) and 51.55?μg/mL (autumn sample). However, on ADP-induced platelet aggregation, IC50 of these samples were greater than 200?μg/mL. Both total contents of flavonoids and terpene lactones in autumn sample were greater than that in summer sample. Qualitative and quantitative analysis showed that the distribution of chemicals was variation in different harvesting time.     

川芎嗪衍生物的设计、合成及抗血小板凝集活性研究

分别以川芎嗪(TMP)和邻苯二胺为起始原料,经KMn O4氧化、酯缩合、环化、还原等步骤合成了7个新型的川芎嗪衍生物,其结构经1H NMR、13C NMR及HRMS确证。并采用Born比浊法初步测试了化合物的体外抗血小板凝集活性。结果表明,化合物3和7对二磷酸腺苷(ADP)诱导的血小板凝集抑制率IC50分别为0.23mmol/L和0.27mmol/L,优于母体化合物川芎嗪(0.42mmol/L)。