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基于抗菌氟喹诺酮的作用机制, 一个有效的转化其抗菌活性到抗肿瘤活性的修饰途径被进一步发展。用稠杂环均三唑并噻二嗪作为环丙沙星 (CFX) 羧基的生物电子等排体, 设计合成了1-环丙基-6-氟-7-哌嗪-1-基- 3-(6-取代苯基-7H-[1, 2, 4]三唑并[3, 4-b][1, 3, 4]噻二嗪-3-基)-喹啉-4(1H)-酮 (5a~5e) 及相应的N-乙酰稠杂环化合物 (6a~6e)。同时发现, 均三唑并噻二嗪在热醋酐中可发生噻二嗪环的缩环挤出硫反应到相应的三乙酰化吡唑并均三唑新稠环体系 (7a~7e)。用MTT法评价了新稠杂环化合物对L1210、CHO和HL60 3种癌细胞株的体外生长抑制活性。结果表明, 15个供试化合物的活性 (IC50 < 25 μmol·L−1) 均显著高于母体化合物CFX的活性(IC50 > 150 μmol·L−1), 而且活性按7a~7e > 5a~5e > 6a~6e顺序递减。 相似文献
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桑叶中的黄酮类化合物 总被引:5,自引:0,他引:5
为了研究桑叶的化学成分与生物活性之间的相关性, 采用硅胶、Sephadex LH-20、RP-C18等色谱方法分离纯化, 通过核磁共振谱、质谱等波谱分析手段鉴定化合物结构。从长穗桑的95%乙醇提取物中分离到4个Diels-Alder类加合物, 分别鉴定为mulberrofuran F1 (1)、mulberrofuran F (2)、chalcomoracin (3) 和kuwanon J (4); 2个查耳酮类化合物, 鉴定为morachalcone A (5) 和isobavachalcone (6); 3个黄酮类化合物, 鉴定为 norartocarpetin (7)、kuwanon C (8) 和6-geranylapigenin (9)。化合物1和6为首次从该种植物中分离, 化合物4~5、7~9为首次从桑叶中分离得到, 其中化合物1为新化合物。采用MTT法对化合物1~5进行了抗肿瘤活性筛选, 结果显示化合物1~3对人肿瘤细胞A549、Bel7402、BGC823、HCT-8以及A2780具有抑制作用。 相似文献
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糙海参中具有抗真菌活性的三萜皂苷(英文) 总被引:2,自引:0,他引:2
为了研究糙海参体内的化学成分,寻找结构新颖具有抗真菌活性的三萜皂苷类成分。应用多种色谱分离技术对糙海参体内的化学成分进行分离纯化,根据化合物的理化性质、波谱数据及化学方法鉴定其结构。分离得到3个三萜皂苷化合物,分别为scabraside A (1)、echinoside A (2) 和holothurin A1 (3),并对其抗真菌活性进行了研究 (1≤MIC80≤16 μg·mL−1)。化合物1为新的三萜皂苷化合物,化合物2和3为首次从该海参中分离得到,它们均显示显著的抗真菌活性。 相似文献
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N-取代苯甲酰胺类衍生物的合成与抗肿瘤活性 总被引:1,自引:0,他引:1
为寻找新型具有抗肿瘤活性的组蛋白去乙酰化酶 (HDACs) 抑制剂, 合成了HDACs抑制剂MS-275, 并以其为先导结构设计合成了11个N-取代苯甲酰胺类目标化合物, 测定体外抗肿瘤及抑酶活性。MS-275及目标化合物的结构经1H NMR及HR-MS分析确证。体外抑HDAC活性研究表明, 化合物9d的抑酶活性与阳性对照药MS-275相当, 值得进一步深入研究; 化合物5c、5d和9c表现出明显量效关系, 具有一定抑酶活性。在对各细胞株的体外抗增殖作用研究中, 发现除9e外, 其他10个化合物显示了对Hut 78的不同抑制活性, 并表现出对Hut 78细胞株具有一定的选择性。 相似文献
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一些重要天然活性环肽化学和生物活性研究进展 总被引:1,自引:0,他引:1
天然环肽化合物以其广泛的分布、新奇的结构和丰富的活性成为化学家和药学家研究的热点。多年的天然产物化学及活性与药物研发已经从天然环肽化合物中发现一批药物, 包括免疫抑制剂环孢菌素A (cyclosporin-A, 1)、抗生素短杆菌肽S (gramicidin-S, 2)、万古霉素 (vancomycin, 3)、达托霉素 (daptomycin, 4) 等; 多个环肽化合物正在进行临床试验研究, 如具有抗肿瘤活性的海洋环肽aplidine (5) 等; 另有数个植物环肽化合物具有良好的成药前景, 如具有抗肿瘤活性的茜草科类型环肽RA-V (6) 和RA-VII (7)、免疫抑制活性的菊科类 型环肽astin-C (8) 等。本文将从分子及其重要活性发现、作用机制、构效关系或结构改造等方面简要介绍以上这些重要天然活性环肽的化学和生物活性研究进展, 期望帮助读者了解天然活性环肽化合物的研究概况。 相似文献
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玉竹中新的高双氢异黄酮 总被引:2,自引:0,他引:2
为了研究玉竹的化学成分, 利用各种柱色谱及高压液相色谱等方法进行分离和纯化, 根据理化性质和光谱数据鉴定化合物结构。从玉竹提取物中分离得到9个化合物, 其中3个为新的双氢高异黄酮类化合物, 分别为5,7-dihydroxy-6-methoxyl-8-methyl-3-(2′,4′-dihydroxybenzyl)chroman-4-one (1), 5,7-dihydroxy-6-methyl-3-(2′, 4′-dihydroxybenzyl)-chroman-4-one (2), 5,7-dihydroxy-6-methoxyl-8-methyl-3-(4′-methoxybenzyl)chroman-4-one (3), 其余化合物分别为disporopsin (4), 柯伊利素 (chrysoeriol, 5), 5,4′-dihydroxy-7-methoxy-6-methylflavane (6), N-trans-feruloyltyramine (7), N-trans-feruloyloctopamine (8), (+)-syringaresinol (9)。化合物1~3为未见文献报道的新化合物, 化合物4~9为该植物中首次分离得到。 相似文献
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丙二酸类PTP1B抑制剂的设计、合成及活性研究 总被引:1,自引:0,他引:1
蛋白酪氨酸磷酸酶 (protein tyrosine phosphatase, PTP) 1B是治疗2型糖尿病 (T2DM) 及肥胖症的潜在靶点。磷酸酪氨酸 (pTyr) 是PTP1B去磷酸化作用的底物, 本文以丙二酸基团模拟pTyr分子中的磷酸酯, 设计合成了丙二酸类PTP1B抑制剂1~7。抑酶活性评价显示, 化合物3和4对人重组PTP1B的半数抑制浓度IC50分别为7.66和1.88 μmol·L−1。 相似文献
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《Toxicology in vitro》2010,24(5):1347-1355
As flavonoids, chalcones possess a wide variety of biological activities including anticancer properties. In the present study we have investigated the in vitro antiproliferative and antiangiogenic effects of four synthetic chalcones.E-2-(4′-methoxybenzylidene)-1-benzosuberone (3) was the most active compound with IC50 = 10−7 mol l−1 in Jurkat cells. In both Jurkat and HeLa chalcone 3-treated cells we found a significant increase in the proportion of cancer cells in the G2/M phase of the cell cycle as well as an increase in cells having sub-G0/G1 DNA content which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by annexin V staining and DNA fragmentation. These effects were associated with reduced expression of the anti-apoptotic gene, Bcl-2, and increased expression of the pro-apoptotic gene, Bax.Furthermore, chalcone 3 was selected to evaluate its effect on some angiogenic events. In non-toxic concentrations, chalcone 3 inhibited VEGF-induced migration of human umbilical vein endothelial cells. Moreover, it also decreased secretion of matrix metalloproteinase (mainly MMP-9) and vascular endothelial growth factor (VEGF).In conclusion, the present study has assessed the in vitro antiproliferative/antiangiogenic potential of chalcone 3. This results generate a rationale for in vivo efficacy studies with this compound in preclinical cancer models. 相似文献
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Src与iNOS为肿瘤发生、转移中位于不同通路的重要靶酶,本文采用分子拼合的药物设计原理,设计合成了全新的酪氨酸Src蛋白激酶与iNOS的双重抑制剂。所设计合成的化合物经过Src激酶和iNOS的抑制活性检测及体外抗肿瘤测试,实验结果表明大部分化合物对于两种靶酶均表现出一定的抑制活性,部分化合物对于多种肿瘤细胞的增殖有一定的抑制作用。其中化合物33对Src激酶和iNOS均有比较好的抑制活性,对于肝癌HepG2和结肠癌HT-29细胞的增殖也有明显的抑制作用。 相似文献
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Dajun Zhang Xingyue Ji Rongmei Gao Huiqiang Wang Shuai Meng Zhaojin Zhong Yuhuan Li Jiandong Jiang Zhuorong Li 《药学学报(英文版)》2012,2(6):575-580
A novel class of thioflavone and flavonoid derivatives has been prepared and their antiviral activities against enterovirus 71 (EV71) and the coxsackievirus B3 (CVB3) and B6 (CVB6) were evaluated. Compounds 7d and 9b showed potent antiviral activities against EV71 with IC50 values of 8.27 and 5.48 μM, respectively. Compound 7f, which has been synthesized for the first time in this work, showed the highest level of inhibitory activity against both CVB3 and CVB6 with an IC50 value of 0.62 and 0.87 μM. Compounds 4b, 7a, 9c and 9e also showed strong inhibitory activities against both the CVB3 and CVB6 at low concentrations (IC50=1.42?7.15 μM), whereas compounds 4d, 7c, 7e and 7g showed strong activity against CVB6 (IC50=2.91–3.77 μM) together with low levels of activity against CVB3. Compound 7d exhibited stronger inhibitory activity against CVB3 (IC50=6.44 μM) than CVB6 (IC50>8.29 μM). The thioflavone derivatives 7a, 7c, 7d, 7e, 7f and 7g, represent a new class of lead compounds for the development of novel antiviral agents. 相似文献
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Jianwen Yao Jing Chen Zuopeng He Wei Sun Hao Fang Wenfang Xu 《Medicinal chemistry research》2013,22(8):3959-3968
A series of novel sorafenib derivatives containing diaryl thiourea and thioether, 9a–u, was designed and synthesized, and their antiproliferative activities against HCT116 and MDA-MB-231 cell lines were also evaluated and described. Most compounds exhibited potent antiproliferative activity against HCT116 cells with IC50 = 1.8–80.4 μM. Compounds 9p, 9r, and 9s demonstrated competitive antiproliferative activities to sorafenib, against all two cancer cell lines. The structures of all the newly synthesized compounds were determined by 1H NMR, 13C NMR, and HRMS, and compound 9n was characterized by single-crystal X-ray diffraction. Primary structure–activity relationships (SAR) have also been established. 相似文献
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Ratchanok Pingaew Supaluk Prachayasittikul Somsak Ruchirawat Virapong Prachayasittikul 《Medicinal chemistry research》2014,23(4):1768-1780
A new series of 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamide derivatives 5 were synthesized through the Click approach and evaluated for their cytotoxic activity against four cancer cell lines (HuCCA-1, HepG2, A549, and MOLT-3). Most of the synthesized triazoles 5 displayed cytotoxicity against MOLT-3 cell line, except for analogs 5a–c and 5e. Significantly, 4-phenyltriazoles (5a and 5n), 4-(naphthalen-2-yloxy)methyltriazole 5d, as well as 4-((2-oxo-2H-chromen-7-yl)oxy)methyltriazole 5l showed higher cytotoxic activity against HepG2 cells than the reference drug, etoposide. Interestingly, the 4-phenyltriazole 5a was the most potent and promising compound with IC50 value of 9.07 μM against HepG2 cell line. The analog 5a also exerted the highest cytotoxic activity against HuCCA-1 cells. This finding provides the novel lead molecules for further development. 相似文献
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《药学学报(英文版)》2022,12(4):1963-1975
As a member of cyclic nucleotide phosphodiesterase (PDE) enzyme family, PDE10A is in charge of the degradation of cyclic adenosine (cAMP) and guanosine monophosphates (cGMP). While PDE10A is primarily expressed in the medium spiny neurons of the striatum, it has been implicated in a variety of neurological disorders. Indeed, inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system (CNS) pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component. A PDE10A-targeted positron emission tomography (PET) radioligand would enable a better assessment of the pathophysiologic role of PDE10A, as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate, thus accelerating the development of effective PDE10A inhibitors. In this study, we designed and synthesized a novel 18F-aryl PDE10A PET radioligand, codenamed [18F]P10A-1910 ([18F]9), in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination. [18F]9 possessed good in vitro binding affinity (IC50 = 2.1 nmol/L) and selectivity towards PDE10A. Further, [18F]9 exhibited reasonable lipophilicity (logD = 3.50) and brain permeability (Papp > 10 × 10?6 cm/s in MDCK-MDR1 cells). PET imaging studies of [18F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics. Preclinical studies in rodents revealed an improved plasma and brain stability of [18F]9 when compared to the current reference standard for PDE10A-targeted PET, [18F]MNI659. Further, dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of [18F]9 for evaluating target occupancy in vivo in higher species. In conclusion, our results indicated that [18F]9 is a promising PDE10A PET radioligand for clinical translation. 相似文献
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为了寻找新型γ-氨基丁酸 (γ-aminobutyric acid, GABA) 类抗癫痫药物, 以抑制性神经递质γ-氨基丁酸受体 (GABAR) 为作用靶点, 以GABA为原料设计合成了一类全新结构类型的4-(2-乙酰氧基苯甲酰氨基) 丁酰胺类化合物 (5a~5l), 通过IR、1H MNR、EI-MS及元素分析确证了目标化合物的结构。初步药理活性评价结果表明, 目标化合物具有良好抗癫痫活性, 值得进一步研究, 在此基础上, 初步讨论了该类化合物的构效关系。 相似文献
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Design,synthesis and cytotoxic evaluation of nitric oxide‐releasing derivatives of isosteviol
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Twenty‐six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control. The results showed that seven furoxan‐based derivatives ( 8a , 8b , 8c , 8d , 8e , 9e , and 9f ) exhibited desirable cytotoxic activities, while NONOate‐based derivatives displayed poor potency because of unstability. Compared with sunitinib, compounds 8a and 8e were more active on all tested cell lines, especially in HCT116 ( 8a , IC50 = 0.48 ± 0.02 μm ; 8e , IC50 = 0.94 ± 0.01 μm ); compounds 8b and 8d were more potent on HCT116 (IC50 = 3.39 ± 0.06 and 3.29 ± 0.03 μm ), HepG2 (IC50 = 1.05 ± 0.03 and 5.37 ± 0.08 μm ), and SW620 (IC50 = 1.33 ± 0.02 and 4.11 ± 0.05 μm ) cell lines, and 8c exhibited higher activities on HepG2 cells with an IC50 = 4.76 ± 0.14 μm . NO‐releasing experiment of compounds 8a – e , 17a , 18a , 19a , and 21a reminded us that NO‐releasing amount of this series of isosteviol derivatives positively correlates with their cytotoxic activities. 相似文献