二氢哒嗪酮类化合物的合成及其抗血小板聚集活性研究

目的：合成新的哒嗪酮类化合物，并研究其抗血小板聚集活性。方法：在6-（4-氯乙酰氨基苯基）-4，5-二氢-3（2H）-哒嗪酮侧链引入不同取代的哌嗪，合成了一系列化合物，采用^1H-NMR、IR及元素分析等方法确证其结构。采用Born比浊法进行体外抗血小板聚集药理实验。结杲：合成的10个化合物都具有一定的抗血小板凝集的活性，其中化合物4的抗血小板聚集活性明显优于先导化合物MCI-154。结论：4-位取代哌嗪环基的引入对哒嗪酮类化合物抗血小板聚集的活性有显著影响。     

4-甲氧基-1,3-苯二磺酸酯类化合物的合成及其体外抗血小板聚集活性

目的为寻找新的更高活性的抗血小板聚集药物,设计制得10个具有4-甲氧基-1,3-苯二磺酸酯结构的目标化合物(系列2);并对其进行体外活性筛选,评价其抗血小板聚集活性并推测其构效关系。方法按照前期工作获得的吡考他胺衍生物构效关系原则,进行了目标物设计合成,其结构均经~1H-NMR、IR和MS谱确证。采用Born比浊法对目标化合物进行了体外抗血小板聚集活性初筛。结果与结论合成的目标化合物均未见文献报道,其中PS27的活性最高,超过两个阳性对照药物吡考他胺和阿司匹林;PS22、PS23、PS24和PS26等4个化合物的活性优于或与对照药物相当。与磺酰胺类化合物相比,磺酸酯类中具有活性的化合物比例更高,在抗血小板聚集方面具有研究价值。     

Synthesis and antiplatelet activity of new imidazole-4-carboxylic acid derivatives

1-Arylalkyl-5-phenylsulfonamino-imidazole-4-carboxylic acid esters and their carboxamides with an additional secondary amino group were synthesized and identified as antiplatelet agents in a low micromolar range (Born-test, inducer collagen). To describe the mechanism of action more precisely the Born-test was carried out as well with ADP, adrenaline or PAF, respectively. In addition, two compounds were investigated for their COX-1 inhibitory activities. Provided the essential structural criteria are met i.e. amide group or ester, sulfonylamino rest, hydrophobic moieties, and a secondary amino function, slight structural modifications are able to shift the pattern of activity among the above platelet receptors. So, the ester 5c exhibits PAF antagonistic activity at IC(50) = 1 microM and COX-1 inhibition (IC(50) = 0.4 microM). The carboxamide 6c shows ADP antagonistic properties (IC(50) = 2 microM). Compound 6g is as well PAF antagonistic (IC(50) = 4 microM) and a COX-1 inhibitor (IC(50) = 1 microM). The derivative 6i shows a strong antiadrenergic (IC(50) = 0.15 microM) and PAF antagonistic (IC(50) = 0.66 microM) effect.     

Synthesis and antitumor activity of new derivatives of xanthen-9-one-4-acetic acid

Xanthen-9-one-4-acetic acid (XAA) analogues in which the substituents in positions 5 and 6 are included in cyclic structures are described. Direct in vitro toxicity of the synthesized compounds against four tumor cell lines was evaluated, and their ability to stimulate mouse peritoneal macrophages and human monocytes in culture to become tumoricidal (indirect toxicity) was also studied. Despite low direct toxicity, almost all the compounds proved to be able to significantly enhance the lytic properties of both murine macrophages and human monocytes as well as the parent compound XAA and its most active derivative DMXAA taken as reference. In particular, compounds 4a, 5a, 7a, 13a,b, and 16a,b showed higher activity than the lead compound on human monocytes, compound 7a being 2.5 times more active than DMXAA, which is the most potent compound synthesized so far. Moreover, compounds 4a, 5a, 7a, 13a, 16a, and 16b proved to be able to induce TNF production in human immune cells.     

Synthesis and anticoagulant activity of 4-hydroxyquinol-2-one-3-carbonamides

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 24, No. 4, pp. 31–32, April, 1990.     

4-乙氧基-1,3-苯二甲酰胺类化合物的合成及抗血小板聚集活性评价

目的设计并合成4-乙氧基-1,3-苯二甲酰胺类化合物并进行体外抗血小板聚集活性测试。方法以2,4-二甲基苯酚为原料,经Williamson反应、氧化、氯代和胺解反应制得化合物1a～1h,8个目标化合物结构均经~1H-NMR、~(13)C-NMR、IR和MS谱确证。1a～1h分别以ADP和collagen为诱导剂,以吡考他胺和阿司匹林为对照药物,用Born比浊法进行体外抗血小板聚集活性初筛。结果以ADP为诱导剂时化合物1g的活性和以collagen为诱导剂时化合物1a的活性均高于对照药吡考他胺和阿司匹林。结论大多数目标化合物具有较高的体外抗血小板聚集活性,其中,侧链苯环4-位引入位阻较大的烷基正丁基和叔丁基时,活性明显高于位阻较小的烷基取代的目标化合物。     

N~1,N~3-二苯甲基-4-甲氧基-1,3-苯二磺酰胺类化合物的合成及体外抗血小板聚集活性

目的合成作用更强、选择性更好的血小板聚集抑制剂。方法按照前期吡考他胺衍生物的构效关系,设计了新的4-甲氧基-1,3-苯二磺酰胺类化合物,以苯甲醚为原料,通过磺酰化反应和胺解反应制得目标化合物。以吡考他胺(picotamide)、阿司匹林(aspirin)和氯吡格雷(clopidogrel)为阳性对照药物,采用Born比浊法进行体外抗血小板聚集活性初筛,并与具有相同母体结构的7个二取代苯基类化合物进行抗血小板聚集活性评价和比较。结果与结论合成了10个未见文献报道的新化合物,其结构均经13C-NMR、1H-NMR、IR和MS谱确证。在1.3μmol·L~(-1)时,5个化合物(1a、1b、1c、1e、1f)具有抗ADP诱导的家兔体外血小板聚集作用,且优于阳性对照药阿司匹林;化合物1b和1e的抑制活性优于阳性对照药吡考他胺;其中,活性最好的化合物1b的抑制率(62.3%)超过氯吡格雷(55.6%)。两个系列化合物的活性对比表明,新合成的目标化合物中具有抗血小板聚集活性的化合物的数目更多,此类化合物有进一步研究的价值。     

三唑硫酮双席夫碱类衍生物的合成及抗肿瘤活性研究

目的：设计和合成一系列新的1,2,4-三唑-5-硫酮双席夫碱类衍生物并测定其抗肿瘤活性。方法以3,4,5-三甲氧基苯甲醛和甘氨酸为原料经一系列反应合成目标化合物7a ～7g,经氢谱核磁共振（1 H - NMR）和红外光谱（IR）表征后在 HeLa、HCT116及 BEL -7402细胞中用噻唑蓝（MTT）法测定其抑制细胞增殖的程度初步判断化合物的体外抗癌活性。结果相对于阳性对照药顺铂,化合物7a、7b、7d、7e 和7g 对 HCT116细胞显示出显著的增殖抑制活性,7a 和7d 对 HeLa 细胞有明显的增殖抑制活性,而7d 对 BEL -7402细胞有很强的抑制作用。结论化合物7d 对3种肿瘤细胞都有显著的抑制增殖活性,但其他化合物对不同来源肿瘤细胞显示出不同的抑制能力。     

Asperphenamate衍生物的合成及体外抗乳腺癌活性评价

目的 设计合成天然产物asperphenamate衍生物。并对其体外抗人乳腺癌作用进行评价。方法 以L-苯丙氨酸为起始原料,经过4 步反应得到目标产物,其结构经核磁共振氢谱确证。采用MTT方法,以T47D和MDA-MB231细胞为实验瘤株进行体外抗乳腺癌活性测试。结果与结论 设计合成了27个新化合物。体外抗乳腺癌活性测试结果表明,化合物NPED-6和NPED-19的体外抗乳腺癌活性明显强于苯丙氨酸片段手性中心消旋的asperphenamate,它们的半数抑制浓度接近10 μmol·L^-1。     

Synthesis and tuberculostatic activity of derivatives of 1,2,4-triazol-3-thione

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 25, No. 3, pp. 25–27, March, 1991.     

芳酰胺基噻唑类衍生物的合成及其 CCR4趋化抑制活性研究

目的 设计并合成芳酰胺基噻唑类衍生物,测定其体外对CCR4 的趋化抑制作用,期望发现结构新颖的CCR4小分子抑制剂。方法 以1,3-二氯丙酮和硫脲为起始原料,经5步反应制得目标化合物;采用Boyden小室法研究目标化合物对(句噬细胞源趋化因子)MDC通过CCR4所介导的趋化HEK293细胞的抑制作用。结果与结论 合成了11个未见文献报道的新化合物,其结构均经核磁共振氢谱和质谱确证。生物活性初步评价结果显示,该类化合物对CCR4细胞趋化作用具有一定的抑制作用。     

Synthesis and biological activity of substituted 4-aryl-2-methylenehydrazino-4-oxobut-2-enoic acids and their derivatives

Aseries of substituted 2-methylenehydrazino-4-aryl-4-oxobut-2-enoic acids and their anilides and esters were obtained using reactions of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and their amides and esters with benzophenone hydrazone, benzyl monohydrazone, and triphenylphosphazines. The methyl ester of 2-(1,2-diphenyl-2-oxoethylidenehydrazino)-4-(4-chlorophenyl)-4-oxobut-2-enoic acid was also synthesized by decyclization of 3-(1,2-diphenyl-2-oxoethylidenehydrazino)-5-(4-chlorophenyl)-3H-furan-2-one using methanol. The synthesized compounds exhibit moderate anti-inflammatory, analgesic, and antimicrobial activity.     

Synthesis and pharmacological evaluation of novel beta-nitrostyrene derivatives as tyrosine kinase inhibitors with potent antiplatelet activity

Protein tyrosine kinases have been known to be involved in regulation of platelet aggregation, suggesting a potential target for antiplatelet therapy. Our previous study showed that 3,4-methylenedioxy-beta-nitrostyrene (MNS) prevented platelet aggregation caused by various stimulators, and this action was accompanied by inhibition of tyrosine kinases. In the present study, in order to examine the structural determinants required for the actions of MNS and to develop more potent tyrosine kinase inhibitors and antiplatelet agents, a new series of beta-nitrostyrene derivatives were synthesized and pharmacologically characterized. The beta-nitrostyrene derivatives inhibited thrombin- or collagen-induced human platelet aggregation, ATP secretion, GPIIb/IIIa activation and protein tyrosine phosphorylation. In recombinant enzyme assay, some beta-nitrostyrene derivatives also demonstrated potent inhibition of Src and/or Syk kinase activity. Furthermore, there was a good correlation between the inhibitory potency of these compounds on tyrosine kinases and on platelet activation/aggregation. Among them, a benzoyl ester derivative (compound 10) possess up to 8-fold greater potency than MNS and over two orders of magnitude greater potency than genistein or tyrphostin A47 in inhibiting platelet responses to thrombin. Our data suggest that beta-nitrostyrenes may represent a new class of tyrosine kinase inhibitors with potent antiplatelet activity.     

4-甲氧基-1,3-苯二磺酰胺系列化合物的合成及体外抗血小板聚集活性的研究

目的为发现新的抗血小板聚集化合物,参照吡考他胺及其衍生物的构效关系,按照电子等排理论,设计新的4-甲氧基-1,3-苯二磺酰胺类化合物。方法以吡考他胺为先导化合物,通过对其1,3-位两个侧链进行结构改造,进行目标化合物结构设计。以苯甲醚为起始原料,与氯磺酸反应制得中间体4-甲氧基-1,3-苯二磺酰氯,与相应不同取代苯胺进行胺解反应得到目标化合物。目标化合物的结构经~1H-NMR、ESI-MS、IR和~(13)C-NMR谱确证。以吡考他胺和阿司匹林为阳性对照药,以ADP(二磷酸腺苷)为诱导剂,采用Born比浊法进行目标化合物的体外抗血小板聚集活性筛选。结果合成了9个未见报道的4-甲氧基-1,3-苯二磺酰胺类化合物(3a-3i)。在1.30μmol·L~(-1)浓度下,各化合物具有不同的抗血小板聚集活性,其中化合物3d的活性最高。结论侧链引入杂环取代基的化合物活性较高;苯基上连有强吸电子基的化合物的活性较高。