3-取代吲哚-2-酮类化合物的设计、合成及抗肿瘤活性研究

目的设计合成对微管蛋白和血管内皮细胞生长因子受体2(VEGFR-2)激酶具有双重抑制作用的3-取代吲哚-2-酮类化合物,考察其体外抑瘤活性。方法以取代的苯胺为起始原料,经缩合、环合、还原、取代等反应制得系列目标化合物,并考察该系列化合物对微管蛋白和肿瘤细胞的抑制活性。结果共合成了11个新的目标化合物。实验结果显示,化合物j9对微管蛋白和VEGFR-2激酶具有双重抑制活性。所有目标化合物对3种肿瘤细胞株均有中等强度的抑制活性。结论该类化合物是一类具有多靶点作用的抗肿瘤化合物。     

新型吲哚类胆固醇酯转运蛋白抑制剂的设计、合成及生物活性研究

目的设计并合成一系列以吲哚为母核的新型小分子胆固醇酯转运蛋白(CETP)抑制剂,并初步评价其体外抑制活性。方法以实验室前期获得的化合物Ⅰ为先导化合物,主要对其吲哚母环的2,3,5位进行修饰改造。以吲哚-2-羧酸乙酯衍生物为原料,通过还原、氧化、还原胺化、取代、Suzuki偶联、亲核取代反应制备得到8个目标化合物;以吲哚或吲哚-2-羧酸乙酯为原料,经Vilsmeier反应在3位引入醛基,再经过还原胺化、取代、Suzuki偶联、亲核取代得到7个目标化合物;进一步通过对2位酯基水解或经还原、烷基化得到另外2个目标化合物。采用BODIPY-CE荧光分析法,以anacetrapib为阳性对照药,测试目标化合物体外对CETP的抑制活性。结果与结论合成了17个未见报道的新化合物,结构经~1H-NM R、M S、~(13)C-NM R谱确证;活性测试表明该类化合物具有中等强度的CETP抑制活性,其中化合物10h的活性较先导化合物有接近10倍的提高,为今后该类化合物的结构优化提供了重要指导。     

含嘌呤骨架的EGFR双突变体抑制剂的合成及其活性评价

目的设计、合成含嘌呤骨架的EGFR双突变体抑制剂,并评价其抗肺癌细胞增殖活性。方法以2,4-二氯-5-硝基嘧啶和相应的胺为起始原料,合成中间体1a～1d;以2-甲氧基-4-氟-5-硝基苯胺为原料,经氨基保护、亲核取代、还原、亲核取代、脱保护基后,与中间体1a～1d进行亲核取代反应,再经还原、亲核加成-消除反应合成目标化合物TM1～TM4。采用MTT法评价目标化合物对3种人非小细胞肺癌细胞(A549、HCC827、H1975)增殖抑制活性;采用ADP-Glo法评价目标化合物抑制EGFR~(L858R/T790M)激酶活性。结果与结论合成了4个未见文献报道的新化合物,其结构均经1 H-NMR和LC-MS谱确证。体外活性测试结果表明,TM1、TM2、TM4显示出较强的抗H1975和HCC827细胞增殖活性;4个目标化合物对EGFR突变细胞(HCC827和H1975)的抑制活性均强于对EGFR野生型(WT)的细胞(A549);TM1和TM2抑制EGFR~(L858R/T790M)的IC50值分别为2.5、 2.0nmol·L~(-1),与阳性药AZD9291(3.5nmol·L~(-1))相当。以嘌呤为骨架,设计合成的目标化合物对EGFR双突变的细胞有较强的抑制活性;目标物TM1和TM2对EGFR~(L858R/T790M)激酶显示出强的抑制作用。     

新型噁唑烷酮类化合物的合成及其抗凝血活性测试

目的 合成一系列新型噁唑烷酮类化合物并考察其抗凝血活性.方法 以利奈唑胺为先导化合物,采用Me-too策略,以(R)-N-{[(3-氟-4-羟基苯基)-2-氧代噁唑烷-5-基]甲基}乙酰胺l为起始原料,经过两次亲核取代反应,得到目标化合物,通过凝血时间的比较评价化合物活性.结果 合成了6个噁唑烷酮类化合物,其结构经1 H-NMR和MS谱确证.结论 6个化合物均有一定的抗凝血活性.     

2-吲哚醛西佛碱化合物的合成及其抗癌活性研究

目的：合成一系列吲哚-2-位西佛碱衍生物,通过药理筛选寻找具有抗癌活性的化合物。方法：通过亲核取代、还原、氧化、亲核加成等反应得到目的化合物。结果：设计合成了22个吲哚-2-位西佛碱新化合物,药理筛选结果显示2个化合物(5,14)对KB癌细胞株有抑制作用。结论：药理筛选结果表明,一些化合物显示了一定的抗癌活性,值得进一步研究。     

3-取代2-吲哚酮类化合物的合成与抗肿瘤活性研究

目的寻找新的具有血管内皮细胞生长因子受体酪氨酸激酶抑制活性的3-取代2-吲哚酮类化合物。方法以2-吲哚酮为原料，利用缩合反应合成目标化合物，并进行体外初步药效学评价。结果设计并合成了5种化合物，其中4种为首次发现，体外初步药效学研究表明，所合成的化合物均具有抑制S-180肿瘤细胞生长的活性，其中化合物Ⅱ活性最强。结论3-取代2-吲哚酮类化合物具有抑制S-180肿瘤细胞生长的活性，化合物中吲哚环平面与相应的芳环平面之间处于垂直状态时活性较强。     

新型吲哚胺2,3-双加氧酶1抑制剂的合成及活性研究

目的设计合成2类1H-吲唑类新化合物,并测试其吲哚胺2,3-双加氧酶1(IDO1)抑制活性。方法以肿瘤免疫关键调控蛋白IDO1作为靶标,依据IDO1活性位点的关键药效团特征,利用合理药物设计方法,以前期研究获得的高活性化合物作为先导化合物,设计合成了2类1H-吲唑类衍生物,并测试其体外IDO1酶抑制活性。采用分子对接软件DOCK6进行分子对接模拟并分析化合物的构效关系。结果与结论合成了5个1H-吲唑类衍生物,均表现出不同程度的IDO1抑制活性,其中化合物2a和3b的抑制活性较好,在100μmol·L~(-1)时的抑制率均为69%。构效关系和分子对接研究显示,4位连接基团的结构对化合物活性影响很大,1H-吲唑类化合物还有很大结构优化空间,极具开发潜力,可为靶向IDO1的肿瘤免疫治疗提供候选化合物。     

三氮唑骈吡啶类JAK抑制剂的合成及体外活性评价

目的设计合成一系列三氮唑骈吡啶类Janus激酶(JAK)抑制剂并进行初步体外激酶活性评价。方法选择filgotinib为先导化合物,通过结构优化改造,设计合成一系列新型三氮唑骈吡啶类JAK抑制剂。以2-氨基-6-溴-吡啶为起始原料,经过亲核加成、亲核取代、水解、Suzuki偶联、Michael加成等重要反应步骤合成目标化合物。以filgotinib为阳性对照物,采用毛细管电泳方法通过检测底物肽段磷酸化转化率来进行化合物激酶活性评价。结果与结论合成了10个未见文献报道的新化合物,其结构经1H-NMR、MS谱鉴定。初步体外活性评价结果表明,所设计的化合物均表现出一定程度的JAK亚型抑制倾向,其中Ⅰe、Ⅱe两个化合物表现出良好的激酶亚型选择性,具有进一步研究的价值。     

1-（取代）苯磺酰基-3-烷胺基甲基吲哚衍生物的设计合成及其抑酸活性研究

目的设计合成系列1-(取代)苯磺酰基-3-烷胺基甲基吲哚衍生物,评价其对大鼠胃酸分泌的抑制能力,并初步探讨其构效关系。方法以取代吲哚为起始原料,经Vilsmeier反应在吲哚3位引入醛基,再与取代苯磺酰氯反应,最后经还原胺化并成盐制得目标化合物;采用组胺刺激的大鼠胃酸分泌模型评价目标化合物的抑酸活性。结果与结论合成了20个未见文献报道的苯基磺酰基类化合物,目标化合物的结构均经~1H-NMR、~(13)C-NMR和HRMS谱确证。活性测试结果表明,所合成的目标化合物均具有一定的抑酸活性,部分化合物的活性优于阳性药vonoprazan,其中有8个化合物的抑酸率大于80%。     

2,6-二取代氨基-1H-咪唑并[4,5-c]吡啶类化合物的设计合成及JNK2抑制活性研究

目的设计合成2,6-二取代氨基-1H-咪唑并[4,5-c]吡啶类目标化合物并进行体外抑制c-Jun氨基末端激酶2(JNK2)活性测试。方法以2,4-二氯-5-硝基吡啶为起始原料,通过两次与胺类化合物的亲核取代并将硝基还原得到中间体,该中间体与不同取代的苯基异硫氰酸酯反应成环得到目标化合物;以迁移率改变法(mobility shift assay)对目标化合物进行抑制JNK2活性实验。结果与结论合成了13个未见文献报道的新化合物,其结构经~1H-NMR、ESI-MS谱确证,纯度经HPLC测定。目标化合物表现出较好的抑制JNK2活性,其中,化合物TY-1和TY-11抑制JNK2活性与先导化合物(CC-930)相当,2,6-二取代氨基-1H-咪唑并[4,5-c]吡啶类目标化合物具有开发为JNK抑制剂的潜力。     

磺酰胺类抗肿瘤药物研究进展

磺酰胺类药物是药物中重要的一类,有着广泛的生物活性,特别是近年来大量具有抗肿瘤活性的磺酰胺类化合物被报道,其中一些化合物已进入临床试验阶段。尽管这些结构新颖的化合物有一个共同的结构特征,即为芳环或者杂芳环磺酰胺类化合物,但它们的作用机制却表现出多样性,如干扰微管蛋白聚合、阻滞细胞周期正常进行、抑制碳酸酐酶、叶酸依赖性酶、甲硫氨酰氨肽酶和组蛋白去乙酰酶、抑制血管内皮细胞生长因子等。文中根据磺酰胺类化合物的作用靶点,介绍了其在抗肿瘤药物研究中的最新进展。     

血管内皮生长因子受体及其小分子抑制剂的研究进展

目前抗血管生成治疗是抗肿瘤研究的热点.血管内皮生长因子(VEGF)是刺激血管生成的重要因子之一,血管内皮生长因子受体(VEGFR)在肿瘤新生血管中高表达,因此成为肿瘤靶向治疗的理想靶点.以VEGF、VEGFR为靶点的抗肿瘤药物除了常见的单克隆抗体药物阿伐斯汀外,小分子抑制剂舒尼替尼、索拉非尼等也已经广泛使用;另外,一些...     

多重靶向的4-取代苯胺喹唑啉类衍生物抗肿瘤活性研究进展

4-取代苯胺喹唑啉类化合物是喹唑啉类酪氨酸激酶抑制剂中活性较高的一类化合物,其对表皮生长因子受体、血管内皮生长因子受体、组蛋白去乙酰化酶等均有抑制作用,已成为抗肿瘤药物的研究热点。综述了近几年多重靶向的4-取代苯胺喹唑啉类化合物抗肿瘤活性的研究进展。     

Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain-containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC(50) values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC(50) values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC(50) value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.     

Substituted alkylamines and methods of use

This Amgen patent application provides a series of 2-aminoheterocyclic amides described as useful for the treatment of cancer and angiogenesis-related disorders. These compounds appear to be related to a nicotinamide series previously described by Novartis as vascular endothelial growth factor (VEGF) inhibitors. The compounds differ from the Novartis series in that they rely preferentially on an aminobicycloaromatic group at the 2-position of the nicotinamide. Based on the data provided in the application, a 6-amino-(1H) indazole appears to be a particularly important sidechain for these compounds, providing consistent cell activity despite a range of substituted amides at the 3-position of the nicotinamide.     

A combination of liposomal sunitinib plus liposomal irinotecan and liposome co-loaded with two drugs enhanced antitumor activity in PC12-bearing mouse

Pheochromocytomas are highly angiogenic neuroendocrine tumors. The side effects of treatment with cytotoxic agents frequently outweigh the benefits. Neuroendocrine tumors are highly angiogenic, dependent on vascular endothelial growth factor and receptor (VEGFR) activation. Sunitinib has antitumor and antiangiogenic activities that target VEGFRs. We investigated the antitumor activity of liposomal sunitinib and irinotecan alone and in combination. Liposomal sunitinib and irinotecan, and liposomes co-loaded with both drugs were prepared, and antitumor activity and biodistribution were examined in nude mice bearing PC12 tumors. Liposomal sunitinib increased in life span (ILS, 14.3%) compared with free sunitinib (?17.1% ILS) with moderate tumor growth suppression, whereas liposomal irinotecan suppressed tumor growth significantly without a survival benefit compared with free irinotecan (?21.7 and ?13.3% ILSs, respectively). The combination of liposomal sunitinib plus liposomal irinotecan, and liposomes co-loaded with both drugs, induced significant inhibition of tumor growth and increased life-span more than the combination of free drugs. Accumulation of irinotecan in tumors by the combination of the two liposomal drugs and liposomes co-loaded with both drugs was significantly increased compared with the combination of free drugs. This study provides novel formulations of sunitinib and irinotecan in combination for the treatment of pheochromocytoma.     

Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.     

Design, synthesis, antitumor evaluations and molecular modeling studies of novel 3,5-substituted indolin-2-one derivatives

AIM: To design and synthesize a novel class of antitumor agents, featuring the 3, 5-substituted indolin-2-one framework. METHODS: Based on enzyme binding features of (Z)-SU5402, introducing a beta-pyrrole group at the 3-position of the indolin- 2-one core, a series of novel 3,5-substituted indolin-2-ones were designed and synthesized. Four human carcinoma cell lines of A-431, A-549, MDA-MB-468, and Autosomal Dominant Polycystic Kidney disease were chosen for the cell proliferation assay. RESULTS: Twenty new compounds (1a-t) with E configuration have been designed, synthesized and bioassayed. Their structural features were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra, and confirmed by X-ray crystallography. Although the enzyme assay showed a weak inhibition effect against the epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor tyrosine kinases, the cell-based antitumor activity was promising. Compounds 1 g and 1 h showed higher inhibitory activity toward the A-549 and MDA-MB-468 cell lines with IC(50 ) of 0.065-9.4 micromol/L. CONCLUSION: This study provides a new template for further development of potent antitumor drugs.     

Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors

A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).