共查询到19条相似文献,搜索用时 140 毫秒
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以4-氯-6,7-二甲氧基喹唑啉、8-溴辛酸乙酯及溴代正丁烷等为原料,根据喹唑啉类化合物药效结构关系,对N-(3-氯-4-烷氧苯基)喹唑啉-4-胺类化合物(ARRY-334543)进行了结构修饰,合成了具有抗肿瘤细胞活性的酪氨酸激酶抑制剂。采用NMR和MS对化合物的结构进行了表征,并对其进行了抗肿瘤细胞活性测试。得到的化合物IX a ~ b均对MCF-7、BGC-823、A549、DU145和H1975细胞有一定的抗肿瘤活性,活性最好的是化合物IX a,其半数抑制浓度(GI50)为0.37μmol/L。 相似文献
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蛋白酪氨酸激酶是一类具有酪氨酸激酶活性的蛋白质,其异常表达与肿瘤的侵袭、转移以及肿瘤新生血管的生成等密切相关。以蛋白酪氨酸激酶作为靶点的药物研究已取得了突破性进展,目前已有二十余个小分子蛋白酪氨酸激酶抑制剂用于临床肿瘤的治疗,并有大量的抑制剂处于临床前和临床研究阶段。对近年来小分子蛋白酪氨酸激酶抑制剂的研究进展进行了综述。 相似文献
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对2-(3-甲基-6-甲氧基喹唑啉-2-氨基)-6-(1-苯基-1H-四唑-5-硫甲基)-4-嘧啶酮(DCE-254)进行了分子对接,设计、合成了14种DCE-254类似物。以4-氯乙酰乙酸乙酯和1-苯基-5-巯基四氮唑,盐酸胍,取代苯甲酰氯、取代异硫氰酸酯等为原料,合成了这些类似物Va~Ⅵh。采用MS,1HNMR和13CNMR对这些类似物的结构进行了表征。H3K27me放射性甲基化抑制测试得到了5种具有较强甲基化抑制作用的DCE-254类似物,活性最好的是N-[4-羟基-6-(1-苯基-1H-四氮唑-5-硫甲基)-2-嘧啶]-N''-2-甲氧基-5-甲基苯基硫脲(Ⅵf),其甲基化抑制率达到77% 结果优于DCE-254。 相似文献
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以D-苯丙氨酸和D-亮氨酸为起始原料,采用液相合成法,经典的"3+2"合成策略,通过对氨基酸N端的保护及脱保护、C端的脱保护、氨基酸的甲基化、缩合等步骤,以混合缩合试剂DEPBT/HATU/TBTU关环,合成了两个环五肽HW-1和HW-2,化合物结构通过1HNMR,13CNMR,MS和ICP-MS进行表征。采用MTT法对目标产物HW-1和HW-2进行抗肿瘤活性筛选,结果显示其具有良好的活性,尤其对Hep G2的IC50值分别为3.14和9.2 mg/L。 相似文献
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以诺蒎酮为原料,经过加成、缩合、环化等反应,合成出蒎烷基噻唑腙衍生物4a~4n,采用FTIR、1HNMR、13CNMR和HRMS对化合物的结构进行了表征。考察了化合物4a~4n对人肝癌细胞(HepG2)、人多发性骨髓瘤细胞(RPMI-8226)、人肺癌细胞(A549)和乳腺癌细胞(MDA-MB-231)的抗肿瘤活性。实验结果表明,化合物4a的抗肿瘤活性最强,其对Hep G2、8226、A549和231细胞的IC50分别低至5.8、8.8、7.1和10.6μmol/L;化合物4c的抗肿瘤活性也较强,其IC50分别为8.9、8.7、7.3和9.7μmol/L。细胞凋亡和周期实验数据显示,当化合物4a浓度从0增加到40μmol/L时,A549细胞的总凋亡率从6.55%增加到47.20%,G2/M期的细胞数量从13.50%上升至51.72%。以上结果表明,化合物4a能够诱导A549细胞凋亡,并将细胞有丝分裂周期阻滞在G2/M期。 相似文献
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以诺蒎酮为原料,经过加成、缩合、环化等反应,合成出蒎烷基噻唑腙衍生物4a~4n,采用FTIR、1HNMR、13CNMR和HRMS对化合物的结构进行了表征。考察了化合物4a~4n对人肝癌细胞(HepG2)、人多发性骨髓瘤细胞(RPMI-8226)、人肺癌细胞(A549)和乳腺癌细胞(MDA-MB-231)的抗肿瘤活性。实验结果表明,化合物4a的抗肿瘤活性最强,其对Hep G2、8226、A549和231细胞的IC50分别低至5.8、8.8、7.1和10.6μmol/L;化合物4c的抗肿瘤活性也较强,其IC50分别为8.9、8.7、7.3和9.7μmol/L。细胞凋亡和周期实验数据显示,当化合物4a浓度从0增加到40μmol/L时,A549细胞的总凋亡率从6.55%增加到47.20%,G2/M期的细胞数量从13.50%上升至51.72%。以上结果表明,化合物4a能够诱导A549细胞凋亡,并将细胞有丝分裂周期阻滞在G2/M期。 相似文献
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BCR-ABL络氨酸激酶与慢性粒细胞白血病(CML)的发生密切相关,以其为靶点的激酶抑制剂成为近年来抗CML药物的研发热点。与传统药物相比,此类药物具有选择性高、副作用少的特点,部分已经成为治疗慢性粒细胞白血病的一线用药。文章从作用机制、临床适用范围和国内外上市开发状况等方面,对BCR-ABL络氨酸激酶抑制剂类药物的研究进展进行了综述。 相似文献
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Dr. Hui Qiu Zahid Ali Julian Bowlan Richard Caldwell Dr. Anna Gardberg Nina Glaser Dr. Andreas Goutopoulos Jared Head Dr. Theresa Johnson Dr. Christine Maurer Dr. Katrin Georgi Dr. Roland Grenningloh Dr. Zhizhou Fang Dr. Federica Morandi Dr. Felix Rohdich Dr. Ralf. Schmidt Dr. Ariele Viacava Follis Dr. Brian Sherer 《ChemMedChem》2021,16(24):3653-3662
Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors. The top molecule 1 of that series strongly inhibited CYP2C8 (IC50=100 nM), which was attributed to the bridged linker group. However, our effort on the linker replacement turned out to be fruitless. With the study of the X-ray crystal structure of compound 1 , we envisioned the opportunity of removal of this liability via transposition of the linker moiety in 1 from C6 to C5 position of the pyridine core. With this strategy, our optimization led to the discovery of a novel series, in which the top molecule 18 A displayed reduced CYP inhibitory activity and good potency. To further explore this new series, different warheads besides acrylamide, for example cyanamide, were also tested. However, this effort didn't lead to the discovery of molecules with better potency than 18 A . The loss of potency in those molecules could be related to the reduced reactivity of the warhead or reversible binding mode. Further profiling of 18 A disclosed that it had a strong hERG (human Ether-a-go-go Related Gene) inhibition, which could be related to the phenoxyphenyl group. 相似文献
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蛋白络氨酸激酶抑制剂作为目前治疗效果明显而且应用前景广阔的抗肿瘤药物备受青睐。本文以近5年的文献为主要参考,对已经上市的和处于研究阶段的脲类酪氨酸激酶抑制剂进行了综述。 相似文献
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3-羰基-甘遂-8,24-二烯-21-羧酸(KTDA)对某些肿瘤细胞有抑制增殖作用,且曾浓度依赖性。本文将KTDA进行胺化以及酯化得到7个KTDA衍生物,并采用MTT法评价了KTDA以及7个衍生物对SMMC-7721、A549、Eca-109、KB四种肿瘤细胞的体外抗肿瘤活性。衍生物中化合物2对SMMC-7721肿瘤细胞的IC50值比KTDA的IC50值低,化合物8对SMMC-7721、Eca-109肿瘤细胞的Ic50值比KTDA的IC50值低。 相似文献
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Francesca Ragusa Silvia Martina Ferrari Giusy Elia Sabrina Rosaria Paparo Eugenia Balestri Chiara Botrini Armando Patrizio Valeria Mazzi Giovanni Guglielmi Rudy Foddis Claudio Spinelli Salvatore Ulisse Alessandro Antonelli Poupak Fallahi 《International journal of molecular sciences》2022,23(10)
Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient’s individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies. 相似文献
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喹唑啉类化合物具有良好的抗肿瘤活性,主要通过对表皮生长因子受体、血管内皮细胞生长因子受体或其酪氨酸激酶的抑制作用,从而达到抗癌的功效。综述了近年来该类衍生物的合成及其抗肿瘤活性研究进展。 相似文献
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Víctor Albarrn María Luisa Villamayor Jesús Chamorro Diana Isabel Rosero Javier Pozas María San Romn Juan Carlos Calvo Patricia Prez de Aguado Jaime Moreno Patricia Guerrero Carlos Gonzlez Coral García de Quevedo Pablo lvarez-Ballesteros María ngeles Vaz 《International journal of molecular sciences》2022,23(22)
Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies. 相似文献