共查询到17条相似文献,搜索用时 62 毫秒
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《中国药物化学杂志》2019,(4):317-324
磷脂酰肌醇3-激酶δ(PI3Kδ)主要分布在造血细胞和免疫细胞中,对于B细胞的活化、增殖非常重要。PI3Kδ抑制剂可用于免疫相关的疾病与血液肿瘤的治疗。PI3Kδ抑制剂的化学结构多种多样,其中喹唑啉酮类选择性PI3Kδ抑制剂能诱导PI3Kδ构象的改变,是螺旋桨型PI3Kδ抑制剂的代表。本文基于喹唑啉酮类选择性PI3Kδ抑制剂与铰链区结合的结构不同(分为嘌呤类、吡唑并嘧啶类、嘧啶类),对近年来喹唑啉酮类选择性PI3Kδ抑制剂的最新研究进展进行综述。 相似文献
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组蛋白去乙酰化酶(histone deacetylase, HDAC)通常异常过表达,导致肿瘤抑制基因的转录抑制。作为具有巨大潜力的抗癌药物,组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDIs)可以通过调节核小体结构,抑制HDAC活性,调控抑癌基因表达而发挥抗肿瘤效应。目前,已上市的5个HDAC抑制剂适应症局限于外周T细胞淋巴瘤和皮肤T细胞淋巴瘤,而在实体瘤方面,大多数作为单一药物使用的HDAC抑制剂未能得到有效的治疗效果。磷脂酰肌醇3-激酶(phosphoinositide 3-kinase, PI3K)是PI3K-AKT-mTOR信号通路的起始节点,在肿瘤细胞的增殖、迁移、侵袭、分化等过程中起着十分重要的作用,该通路的异常激活与肿瘤的发生发展有着密切关系,将HDAC抑制剂和PI3K抑制剂的联合使用以及HDAC/PI3K双靶点抑制剂能够改善单独用药时存在的问题。本综述介绍了具有代表性的HDIs和PI3K抑制剂,以及HDAC/PI3K抑制剂联用及双靶点抑制剂的抗肿瘤临床和临床前研究进展。 相似文献
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本文通过文献检索和归纳总结,介绍了抗癌靶点分子PI3K及靶向药物PI3K抑制剂的研究进展。PI3K在肿瘤发生中起着关键性作用,因此PI3K抑制剂已成为当前抗癌新药开发的热点。迄今为止,已有包括ZSTK474在内的近20种新型PI3K抑制剂因具有较好的抗肿瘤效果和较低的毒性而被批准进入临床试验。PI3K抑制剂与其他药物的联合治疗试验也已取得较好效果。PI3K抑制剂有望在不远的将来成为一类新型分子靶向药物。 相似文献
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《中国药物化学杂志》2015,(3)
目的改进pictilisib的合成工艺。方法以3-氨基-2-噻吩甲酸甲酯为起始原料,经环合、氯代、取代、甲酰化,制得2-氯-4-(吗啉-4-基)噻吩并[3,2-d]嘧啶-6-甲醛,再经还原、氯代、缩合制得关键中间体2-氯-6-[(4-甲磺酰哌嗪-1-基)甲基]-4-(吗啉-4-基)噻吩并[3,2-d]嘧啶,该中间体与2-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-[1,3,2]-二氧杂硼环戊烷-2-基)-2H-吲唑经Suzuki偶联、脱保护成盐、碱化得到目标化合物。结果与结论目标化合物结构经1H-NMR、13C-NMR、IR及MS谱确证,总收率为34.2%(以3-氨基-2-噻吩甲酸甲酯计)。与文献报道的工艺相比,该路线操作简单、条件温和、收率较高,适用于工业化生产。 相似文献
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《Expert opinion on investigational drugs》2013,22(9):1265-1277
PI3K is an important node regulating the signaling of several essential biological processes. PI3K catalyzes the phosphorylation in position 3 of the inositol ring of phosphatidyl-inositide producing important lipid second messengers. The products of PI3K activity recruit PDK1 and AKT Ser/Thr kinases to the plasma membrane where they get activated transducing a potent proliferative and anti-apoptotic signal to the cell. PI3K is activated by growth factors, insulin and GPCR activation. Furthermore, PI3K can be activated by direct binding to oncogenic Ras proteins. PI3K is commonly altered in human cancers by point activating mutations or by amplification. Furthermore, other proteins of the route are also altered in human tumors (such as phosphatase and tensin homolog in chromosome 10 or human EGF receptor 2) providing constitutive activation of PI3K. The evidence indicates that the PI3K pathway is a potential target for cancer chemotherapy. Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the PI3K pathway at different points. In this work, we review the targeting of PI3K protein for therapeutical intervention. 相似文献
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目的设计合成新的磷脂酰肌醇3-激酶抑制剂,并测定其体外活性。方法通过结构替换、分子对接技术设计一系列邻苯二甲酰亚胺类化合物。以4-溴邻苯二甲酸酐为原料经胺解反应得到N-芳基-4-溴邻苯二甲酰亚胺Ⅰ1~Ⅰ8;Ⅰ1~Ⅰ8再与3-(4-氟苯磺酰胺基)苯硼酸经Suzuki偶联得到N-芳基-4-(3-对氟苯磺酰胺苯基)邻苯二甲酰亚胺Ⅲ1~Ⅲ8;以阿霉素为阳性对照,采用MTT法进行体外活性测定。结果与结论合成了16个未见文献报道的邻苯二甲酰亚胺类化合物,目标化合物的结构经1H-NMR、MS谱确证;体外活性实验结果显示,N-芳基-4-(3-对氟苯磺酰胺苯基)邻苯二甲酰亚胺衍生物具有潜在的抑制肿瘤生长作用,其中,化合物Ⅲ1对A549、MCF-7肿瘤细胞表现出显著的抑制活性,具有进一步研究的价值。 相似文献
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《Expert opinion on therapeutic patents》2013,23(11):1805-1810
A small series of aryl(1-arylamino)ethyl,1,5-naphthyridine derivatives that selectively inhibit PI3Kδ was prepared. The compounds are claimed to be useful in the treatment of cancer, inflammatory and autoimmune diseases. The compounds represent further variations around a structural motif explored in a number of previous applications by the applicant. 相似文献
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目的寻找具有新型骨架结构的磷脂酰肌醇3激酶(PI3K)抑制剂。方法基于活性化合物,利用"杂交"设计原理,设计和合成了系列4-吗啉喹唑啉类衍生物。结果目标化合物经1HNMR、质谱确证结构,并评价了其对Rh30细胞的增殖抑制活性。结论大部分化合物具有较好的抑制活性,化合物8b的活性最强,其IC50达0.8μmol.L-1。4-吗啉喹唑啉是一类新型的PI3K抑制剂骨架,值得进一步进行结构修饰研究。 相似文献
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以含有喹喔啉母核的PI3K抑制剂XL765和WR23为结构基础,通过生物电子等排,在喹喔啉母核上2位引入取代苯氧基片段,延长3位连接链改为磺酰肼,并在7位引入氟原子;去掉3位取代并在7位引入丙烯酰胺基。初步设计并合成了22个喹喔啉类衍生物,通过1H NMR、13C NMR、ESI-MS进行结构确证。以人非小细胞肺癌A549、人乳腺癌细胞MCF-7、人结肠癌细胞HCT-116和人肝癌细胞HepG2进行体外抗肿瘤活性筛选(MTT法)。结果表明, P6b、P6e、P6f对HCT116活性较好(IC50=3.24, 4.78和4.50μmol·L-1), P6d对MCF-7具有较强抑制作用(IC50=0.228 7μmol·L-1)。 相似文献
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The pivotal roles of phosphatidylinositol 3-kinases (PI3Ks) in human cancers have inspired active development of small molecules to inhibit these lipid kinases. However, the first-generation pan-PI3K and dual-PI3K/mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent as well as a relatively high rate of side effects. It is increasingly recognized that different PI3K isoforms play non-redundant roles in particular tumor types, which has prompted the development of isoform-selective inhibitors for pre-selected patients with the aim for improving efficacy while decreasing undesirable side effects. The success of PI3K isoform-selective inhibitors is represented by CAL101 (Idelalisib), a first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of chronic lymphocytic leukemia, indolent B-cell non-Hodgkin''s lymphoma and relapsed small lymphocytic lymphoma. Inhibitors targeting other PI3K isoforms are also being extensively developed. This review focuses on the recent progress in development of PI3K isoform-selective inhibitors for cancer therapy. A deeper understanding of the action modes of novel PI3K isoform-selective inhibitors will provide valuable information to further validate the concept of targeting specific PI3K isoforms, while the identification of biomarkers to stratify patients who are likely to benefit from the therapy will be essential for the success of these agents. 相似文献