嘧啶类酪氨酸激酶抑制剂

酪氨酸激酶在肿瘤的发生、发展过程中起着非常重要的作用,已成为肿瘤治疗的新靶点.嘧啶类化合物是蛋白酪氨酸酶抑制剂(PTKIs)中的一大类,这类化合物在临床前期研究中显示具有很好的抗肿瘤效应,一些已在临床上作为很有前景的抗癌药.本文按其结构类别介绍了近年来报道的嘧啶类酪氨酸激酶抑制剂.     

酪氨酸蛋白激酶抑制剂:亚苄基丙二腈类衍生物定量构效关系的量子化学研究

用量子化学从头算方法,对亚苄丙二腈衍生物的定量构效关系(QSAR)进行了研究,结果显示:指示变量I,偶极矩Dipole和最低空轨道的能量ELUMO对亚苄丙二腈衍生物的抑制活性有很大影响,回归分析得到了相关性好的相关模型(R=0.95).I=0时,亚苄基丙二腈类衍生物的抑制作用由其化学反应性决定;I=1时其抑制作用由其静电性决定.     

多靶点受体酪氨酸激酶抑制剂ABT-869的有效合成方法

ABT-869是结构新型有效的多靶点受体酪氨酸激酶抑制剂,目前正处在III期临床研究阶段.从商业廉价易得的间氟苯胺出发,以较低的成本经过7步反应以42.3%的总收率实现了多靶点受体酪氨酸激酶抑制剂ABT-869全合成.该工艺在关键步骤Suzuki偶联反应中使用了超声波反应器,极大地缩短反应时间,提高了收率,并且该工艺各步反应中间体不用纯化直接投入下步反应,最终产物只需结晶纯化即可达到大于99%的纯度,无需传统的柱层析分离,更适合于工业生产.     

新型吡咯并[2,1-f][1,2,4]三嗪酪氨酸激酶抑制剂的设计与合成

以对甲基苯磺酰甲基异腈和反-2-丁烯酸甲酯为原料,经过11步反应合成了7个4,5,6-三取代的新型吡咯并[2,1-f][1,2,4]三嗪酪氨酸激酶抑制剂,总收率3.2%～10.0%,其结构经1H NMR和MS 表征.     

小分子蛋白酪氨酸激酶抑制剂的合成研究进展

蛋白酪氨酸激酶在肿瘤的形成和增殖中起着关键作用,以蛋白酪氨酸激酶作为肿瘤治疗靶点的研究受到极大关注.本文作者综述了近十年来不同结构的酪氨酸激酶抑制剂的合成以及抗肿瘤活性的研究进展,以期为酪氨酸激酶抑制剂的研究与开发提供参考.     

酪氨酸激酶抑制剂的比较分子场分析

采用比较分子场分析(CoMFA)方法研究了一组嘧啶类衍生物酪氨酸激酶抑制剂活性与结构的关系.所得模型不仅能够很好地预报训练集中的化合物的活性,而且还可以准确地预报预报集中的化合物活性.通过分析分子场等值面图在空间的分布,可以观察到叠加分子周围的立体和静电特征对化合物活性的影响.     

酪氨酸激酶抑制剂的三维定量构效关系研究

利用柔性原子受体模型(FLARM)方法对一系列的异黄酮和喹诺酮衍生物表皮生长因子受体酪氨酸激酶抑制剂进行了三维定量构效关系研究，得到了合理的构效关系模型.FLARM方法的计算结果还给出了虚拟的受体模型，该模型说明了抑制剂与受体之间可能的相互作用.由该虚拟受体模型得到的受体-配体相互作用与Novartis药效团模型比较类似.     

6-氮杂吲唑类Pim-1激酶抑制剂的3D-QSAR、药效团模型研究和分子设计

Pim-1激酶通过作用于多种信号通路或靶点影响肿瘤的发生发展,近年来被认为是肿瘤治疗的良好靶标。本文采用SYBYL-X2.1.1软件中的Topomer CoMFA、GALAHAD模块建立计算机模型,研究39个基于6-氮杂吲唑环的Pim-1激酶抑制剂的三维定量构效关系及药效团特征元素。结果显示,Topomer CoMFA建模所得交叉验证系数(q²)和相关系数(r²)分别为0.756和0.951,结合外部验证表明此3D-QSAR模型具有较高预测能力及较好的统计学稳定性,同时,用等势图描述了R1、R2基团处立体场、静电场对活性的具体影响。药效团研究结果表明,含氢键受体的芳香杂环母核结构,以及侧链取代基中含有芳香杂环结构对化合物的活性贡献较大。最后根据上述模型信息新设计了15个Pim-1激酶抑制剂分子并完成活性预测及分子对接模式研究,其中4个分子的预测pIC₅₀高于建模分子中活性最好的化合物17,Surflex-Dock分析显示新设计分子均与Pim-1激酶形成较强氢键相互作用。基于6-氮杂吲唑环的Pim-1激酶抑制剂的3D-QS...     

含吡唑酮基团的喹唑啉衍生物的合成及其作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂

双靶标酪氨酸激酶抑制剂在克服药物抗性和减少药物毒副作用方面具有重要作用,本文设计并合成了含有吡唑酮基团的喹唑啉衍生物作为EGFR/VEGFR-2双靶标酪氨酸激酶抑制剂。目标化合物由喹唑啉中间体和吡唑酮中间体通过亲核取代反应合成。喹唑啉中间体以2,3,4-三羟基苯甲酸为原料,通过酯化、硝化、还原、氯化和环化等反应合成;吡唑酮中间体以4-取代苯基肼盐酸盐为原料,通过甲基化和氧化等反应合成。目标化合物通过¹H NMR、¹³C NMR和HR-MS进行结构鉴定。分别采用ADP-Glo激酶活性检测方法和CCK-8法测定了目标化合物对EGFR和VEGFR-2的抑制活性以及对Hela细胞、A549细胞、HUVEC细胞的抗增殖活性,其对EGFR和VEGFR-2抑制活性IC₅₀值为10～899 nM, 15～712 nM;对部分在分子水平测定表现出较高活性的化合物进行了抗增殖活性测定,所选定的化合物对人肺癌A549细胞的半抑制浓度IC₅₀值为10～267 nM,对人脐静脉内皮细胞HUVEC的半抑制浓度IC_50...     

Molecular Modeling Studies of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Combining Molecular Docking and 3D-QSAR Methods

The vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases VEGFR-2 or kinase insertdomain receptor (KDR) have emerged as attractive targets for the design of novel anticancer agents. In the present work, molecular docking method combined with three dimensional quantitative structure-activity relationships (comparative molecular field analysis (CoMFA) and comparative molecular similarity indice analysis (CoMSIA)) to analyze the possible interactions between KDR and those derivatives which acted as selective inhibitors. The CoMFA and CoMSIA models gave a cross-validated coefficient Q2 of 0.713 and 0.549, non-cross-validated R2 values of 0.974 and 0.878, and predicted R2 values of 0.966 and 0.823, respectively. The 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. The information obtained from 3D-QSAR and docking studies were very helpful to design novel selective inhibitors of KDR with desired activity and good chemical property.     

Synthesis and Rational Design of New Appended 1,2,3-Triazole-uracil Ensembles as Promising Anti-Tumor Agents via In Silico VEGFR-2 Transferase Inhibition

Angiogenesis inhibition is a key step towards the designing of new chemotherapeutic agents. In a view to preparing new molecular entities for cancer treatment, eighteen 1,2,3-triazole-uracil ensembles 5a–r were designed and synthesized via the click reaction. The ligands were well characterized using ¹H-, ¹³C-NMR, elemental analysis and ESI-mass spectrometry. The in silico binding propinquities of the ligands were studied sequentially in the active region of VEGFR-2 using the Molegro virtual docker. All the compounds produced remarkable interactions and potentially inhibitory ligands against VEGFR-2 were obtained with high negative binding energies. Drug-likeness was assessed from the ADME properties. Cytotoxicity of the test compounds was measured against HeLa and HUH-7 tumor cells and NIH/3T3 normal cells by MTT assay. Compound 5h showed higher growth inhibition activity than the positive control, 5-fluorouracil (5-FU), against both HeLa and HUH-7 cells with IC₅₀ values of 4.5 and 7.7 μM respectively. Interestingly, the compounds 5a–r did not show any cytotoxicity towards the normal cell lines. The results advance the position of substituted triazoles in the area of drug design with no ambiguity.     

Design,synthesis, docking and mechanistic studies of new thiazolyl/thiazolidinylpyrimidine-2,4-dione antiproliferative agents

In this article, we display on the synthesis and biological evaluation of a new series of thiazolylpyrimidine 3a-l and thiazolidinylpyrimidine derivatives 5a-e. The structures of the new compounds were confirmed by using different spectral techniques including NMR, IR, mass spectroscopy in addition to elemental analyses. The cell viability of the new compounds was assessed against normal human mammary gland epithelial (MCF-10A) cell line. Data revealed that none of the compounds examined exhibited cytotoxic effects, and the cell viability for the compounds examined at 50 µM was greater than 87%. The antiproliferative activity of 3a-l and 5a-e was evaluated against four human cancer cell lines where the compounds showed promising activity. The most potent derivatives were compounds 3a, 3c, 3f, 3i, and 5b with GI₅₀ values ranging from 0.90 µM to 1.70 µM against the four cancer cell lines in comparison to doxorubicin (GI₅₀ = 1.10 µM). Compounds 3a, 3c and 3i showed potent antiproliferative activity with dual inhibitory action against EGFR and BRAF^V600E. Compounds 3a, 3c, and 3i demonstrated promising AutoDock scores towards EGFR and BRAF^V600E with values of ? 9.1 and ? 8.6, ?9.0 and ? 8.5, and ? 8.4 and ? 8.0 kcal/mol, respectively. The physicochemical and pharmacokinetic characteristics of 3a, 3c, and 3i were anticipated, demonstrating their oral bioavailability.     

Design,synthesis and evaluation of novel dehydroabietic acid-dithiocarbamate hybrids as potential multi-targeted compounds for tumor cytotoxicity

In the present study, novel representatives of the important group of biologically-active, dehydroabietic acid-bearing dithiocarbamate moiety, were synthesized and characterized by ¹H NMR, ¹³C NMR, HR-MS. The in vitro antiproliferative activity evaluation (MTT) indicated that these compounds exhibited potent inhibitory activities in various cancer cell lines (HepG-2, MCF-7, HeLa, T-24, MGC-803). Particularly, compound III-b possessed extraordinary cytotoxicity with low micromolar IC₅₀ values ranging from 4.07 to 38.84 µM against tested cancer cell lines, while displayed weak cytotoxicity on two normal cell lines (LO-2 and HEK 293 T). Subsequently, the potential mechanisms of representative compound III-b were elementarily investigated by Transwell experiment, which showed III-b can inhibit cancer cells migration. Annexin-V/PI dual staining showed that the compound can induce HepG-2 cells apoptosis in a dose-dependent manner. Meanwhile this apoptosis may be related to the upregulated protein expression of cleaved-caspase 3, cleaved-caspase 9, Bax and downregulated of Bcl-2 indicated by Western Blot. Later study further confirmed that ROS levels in HepG-2 cells increased significantly with the rise of concentrations. In addition, through the network pharmacology data analyzing, the core targets and signaling pathways of compound III-b for treatment of liver neoplasms were forecasted. Molecular docking model showed that compound III-b had high affinity with hub targets (CASP3, EGFR, HSP90AA1, MAPK1, ERBB2, MDM2), suggesting that compound III-b might target the hub protein to modulate signaling activity. Taken together, these data indicated that dehydroabietic acid structural modification following the “Molecular hybridization” principle is a feasible way to discover the potential multi-targeted antitumor compounds.     

Synthesis,pharmacological evaluation,and molecular modeling studies of novel isatin hybrids as potential anticancer agents

A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N₄ piperazine was found to be the most active with the promising IC₅₀ (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.