• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

嘧啶-5-甲腈类潜在抗癌药物通过抑制白血病 K562 中的 PI3K/AKT 轴诱导细胞凋亡。

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562.

机构信息

Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):895-911. doi: 10.1080/14756366.2022.2051022.

DOI:10.1080/14756366.2022.2051022
PMID:35345960
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8967206/
Abstract

A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety -containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds and were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound was promising more than with IC = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚβ. Furthermore, toxicity study indicated good safety profile for . These findings suggest that the trimethoxy derivative has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.

摘要

开发了一系列新型的 4-(4-甲氧基苯基)-2-(甲硫基)嘧啶-5-甲腈，它们与含芳基部分的桥连接在一起，然后评估其对 MCF-7 和 K562 细胞系的细胞毒性活性。七种化合物对两种细胞系均表现出最高的活性，其中化合物 和 对 K562 细胞系的活性最高。通过对 PI3Kδ/γ 和 AKT-1 的酶抑制测定来探索其分子机制表明，化合物 比 更有前途，其 IC = 6.99 ± 0.36、4.01 ± 0.55 和 3.36 ± 0.17 μM。此外，流式细胞术分析显示 导致细胞周期在 S 期停滞，随后 caspase 3 依赖性凋亡诱导。在机制上，化合物 被证明可以调节 PI3K、p-PI3K、AKT、p-AKT、Cyclin D1 和 NFΚβ 的表达。此外， 毒性研究表明 具有良好的安全性。这些发现表明，三甲氧基衍生物 具有作为针对乳腺癌和白血病的 PI3K/AKT 轴的多作用抑制剂的强大潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/65ecf63bcd4c/IENZ_A_2051022_F0011_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/98684bd97f1b/IENZ_A_2051022_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/e7dfcd1b9c63/IENZ_A_2051022_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/0ef08b91cd91/IENZ_A_2051022_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/f595236de8a4/IENZ_A_2051022_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/15fb1b5377e8/IENZ_A_2051022_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/6c084e422fb0/IENZ_A_2051022_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/9a06f22994d7/IENZ_A_2051022_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/7e5d276ddb17/IENZ_A_2051022_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/3d9b84bf809e/IENZ_A_2051022_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/fd08111dd83b/IENZ_A_2051022_F0008_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/213eb329b9cb/IENZ_A_2051022_F0009_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/a2d005814599/IENZ_A_2051022_F0010_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/65ecf63bcd4c/IENZ_A_2051022_F0011_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/98684bd97f1b/IENZ_A_2051022_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/e7dfcd1b9c63/IENZ_A_2051022_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/0ef08b91cd91/IENZ_A_2051022_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/f595236de8a4/IENZ_A_2051022_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/15fb1b5377e8/IENZ_A_2051022_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/6c084e422fb0/IENZ_A_2051022_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/9a06f22994d7/IENZ_A_2051022_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/7e5d276ddb17/IENZ_A_2051022_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/3d9b84bf809e/IENZ_A_2051022_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/fd08111dd83b/IENZ_A_2051022_F0008_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/213eb329b9cb/IENZ_A_2051022_F0009_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/a2d005814599/IENZ_A_2051022_F0010_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8a9/8967206/65ecf63bcd4c/IENZ_A_2051022_F0011_C.jpg

相似文献

1
Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562.嘧啶-5-甲腈类潜在抗癌药物通过抑制白血病 K562 中的 PI3K/AKT 轴诱导细胞凋亡。
J Enzyme Inhib Med Chem. 2022 Dec;37(1):895-911. doi: 10.1080/14756366.2022.2051022.
2
In vitro antiproliferative activity of 2,3-dihydroxy-9,10-anthraquinone induced apoptosis against COLO320 cells through cytochrome c release caspase mediated pathway with PI3K/AKT and COX-2 inhibition.2,3-二羟基-9,10-蒽醌的体外抗增殖活性通过细胞色素c释放的半胱天冬酶介导途径，伴随PI3K/AKT和COX-2抑制，诱导COLO320细胞凋亡。
Chem Biol Interact. 2016 Apr 5;249:23-35. doi: 10.1016/j.cbi.2016.02.016. Epub 2016 Feb 23.
3
Altersolanol B, a fungal tetrahydroanthraquinone, inhibits the proliferation of estrogen receptor-expressing (ER+) human breast adenocarcinoma by modulating PI3K/AKT, p38/ERK MAPK and associated signaling pathways.真菌类四氢蒽醌化合物阿尔特索拉醇 B 通过调节 PI3K/AKT、p38/ERK MAPK 及相关信号通路抑制表达雌激素受体（ER+）的人乳腺腺癌的增殖。
Chem Biol Interact. 2022 May 25;359:109916. doi: 10.1016/j.cbi.2022.109916. Epub 2022 Mar 26.
4
Towards the small and the beautiful: a small dibromotyrosine derivative from Pseudoceratina sp. sponge exhibits potent apoptotic effect through targeting IKK/NFκB signaling pathway.向小而美进军：一种来自拟角蜂巢海绵的小分子二溴酪氨酸衍生物通过靶向 IKK/NFκB 信号通路发挥强大的凋亡作用。
Mar Drugs. 2013 Aug 26;11(9):3168-85. doi: 10.3390/md11093168.
5
Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression.间皮素通过 Akt/PI3K/NF-κB 激活和 IL-6/Mcl-1 过表达赋予胰腺癌细胞对 TNF-α诱导的细胞凋亡的抗性。
Mol Cancer. 2011 Aug 31;10:106. doi: 10.1186/1476-4598-10-106.
6
Benzo[b]furan derivatives induces apoptosis by targeting the PI3K/Akt/mTOR signaling pathway in human breast cancer cells.苯并[b]呋喃衍生物通过靶向人乳腺癌细胞中的PI3K/Akt/mTOR信号通路诱导细胞凋亡。
Bioorg Chem. 2016 Jun;66:124-31. doi: 10.1016/j.bioorg.2016.04.004. Epub 2016 Apr 26.
7
AMR-Me inhibits PI3K/Akt signaling in hormone-dependent MCF-7 breast cancer cells and inactivates NF-κB in hormone-independent MDA-MB-231 cells.AMR-Me抑制激素依赖性MCF-7乳腺癌细胞中的PI3K/Akt信号传导，并使激素非依赖性MDA-MB-231细胞中的NF-κB失活。
Mol Carcinog. 2014 Jul;53(7):578-88. doi: 10.1002/mc.22012. Epub 2013 Mar 8.
8
Casticin induces leukemic cell death through apoptosis and mitotic catastrophe.芫花素通过凋亡和有丝分裂灾难诱导白血病细胞死亡。
Ann Hematol. 2009 Aug;88(8):743-52. doi: 10.1007/s00277-008-0677-3. Epub 2009 Jan 13.
9
Stellettin B induces apoptosis in human chronic myeloid leukemia cells via targeting PI3K and Stat5.链格孢菌素B通过靶向PI3K和Stat5诱导人慢性髓性白血病细胞凋亡。
Oncotarget. 2017 Apr 25;8(17):28906-28921. doi: 10.18632/oncotarget.15957.
10
PI3K/mTOR dual-inhibition with VS-5584 enhances anti-leukemic efficacy of ponatinib in blasts and Ph-negative LSCs of chronic myeloid leukemia.PI3K/mTOR 双重抑制联合 VS-5584 增强了 ponatinib 在慢性髓性白血病原始细胞和 Ph-阴性 LSCs 中的抗白血病疗效。
Eur J Pharmacol. 2021 Nov 5;910:174446. doi: 10.1016/j.ejphar.2021.174446. Epub 2021 Aug 27.

引用本文的文献

1
Unravelling the potency of the 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile scaffold with -arylamide hybrids as PIM-1 kinase inhibitors: synthesis, biological activity and studies.探索以-芳基酰胺杂化物作为PIM-1激酶抑制剂的4-氧代-2-硫代-1,2,3,4-四氢嘧啶-5-甲腈支架的效力：合成、生物活性及研究
RSC Med Chem. 2025 Mar 28. doi: 10.1039/d5md00021a.
2
Non-fused Pyrimidine Derivatives as Potential Pharmacological Entities: A Review.作为潜在药理实体的非稠合嘧啶衍生物：综述
Curr Top Med Chem. 2025;25(9):1032-1068. doi: 10.2174/0115680266317088240924205745.
3
[High expression of CPNE3 correlates with poor long-term prognosis of gastric cancer by inhibiting cell apoptosis activating PI3K/AKT signaling].

本文引用的文献

1
FDA-approved pyrimidine-fused bicyclic heterocycles for cancer therapy: Synthesis and clinical application.FDA 批准的嘧啶并环双杂环化合物用于癌症治疗：合成与临床应用。
Eur J Med Chem. 2021 Mar 15;214:113218. doi: 10.1016/j.ejmech.2021.113218. Epub 2021 Jan 24.
2
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.《全球癌症统计数据 2020：全球 185 个国家和地区 36 种癌症的发病率和死亡率估计》。
CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
3
Virtual Screening of Natural Compounds as Potential PIK-AKT1 Signaling Pathway Inhibitors and Experimental Validation.
CPNE3高表达通过抑制细胞凋亡、激活PI3K/AKT信号通路与胃癌的不良长期预后相关
Nan Fang Yi Ke Da Xue Xue Bao. 2024 Jan 20;44(1):129-137. doi: 10.12122/j.issn.1673-4254.2024.01.15.
4
Novel pyrazolo[3,4-]pyrimidine derivatives: design, synthesis, anticancer evaluation, VEGFR-2 inhibition, and antiangiogenic activity.新型吡唑并[3,4 - ]嘧啶衍生物：设计、合成、抗癌评估、VEGFR - 2抑制及抗血管生成活性
RSC Med Chem. 2023 Nov 7;14(12):2640-2657. doi: 10.1039/d3md00476g. eCollection 2023 Dec 13.
5
Mitigating effect of ferulic acid on di-(2-ethylhexyl) phthalate-induced neurocognitive dysfunction in male rats with a comprehensive in silico survey.阿魏酸对邻苯二甲酸二（2-乙基己基）酯诱导的雄性大鼠神经认知功能障碍的缓解作用：一项综合的计算机预测研究。
Naunyn Schmiedebergs Arch Pharmacol. 2024 May;397(5):3493-3512. doi: 10.1007/s00210-023-02831-9. Epub 2023 Nov 15.
6
Design, Synthesis, and Bioactivities of Novel Trifluoromethyl Pyrimidine Derivatives Bearing an Amide Moiety.含酰胺基团的新型三氟甲基嘧啶衍生物的设计、合成及生物活性
Front Chem. 2022 Jul 15;10:952679. doi: 10.3389/fchem.2022.952679. eCollection 2022.
7
In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers.新型稠合噻吩衍生物作为VEGFR-2/AKT双重抑制剂和凋亡诱导剂的体外抗癌活性筛选
Pharmaceuticals (Basel). 2022 Jun 2;15(6):700. doi: 10.3390/ph15060700.
虚拟筛选天然化合物作为潜在的 PIK-AKT1 信号通路抑制剂及实验验证。
Molecules. 2021 Jan 18;26(2):492. doi: 10.3390/molecules26020492.
4
Identification of a potent and selective phosphatidylinositol 3-kinase δ inhibitor for the treatment of non-Hodgkin's lymphoma.鉴定一种有效的、选择性的磷脂酰肌醇 3-激酶 δ 抑制剂，用于治疗非霍奇金淋巴瘤。
Bioorg Chem. 2020 Dec;105:104344. doi: 10.1016/j.bioorg.2020.104344. Epub 2020 Oct 8.
5
Novel antiproliferative agents bearing morpholinopyrimidine scaffold as PI3K inhibitors and apoptosis inducers; design, synthesis and molecular docking.新型含吗啉嘧啶骨架的抗增殖剂作为 PI3K 抑制剂和凋亡诱导剂；设计、合成与分子对接。
Bioorg Chem. 2020 Sep;102:104051. doi: 10.1016/j.bioorg.2020.104051. Epub 2020 Jun 30.
6
Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells.新型 akt1 抑制剂的发现诱导肝癌细胞自噬相关死亡。
Eur J Med Chem. 2020 Mar 1;189:112076. doi: 10.1016/j.ejmech.2020.112076. Epub 2020 Jan 23.
7
Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.mTORC1/2 抑制剂 vistusertib 联合氟维司群在体外和体内靶向治疗雌激素受体阳性内分泌耐药性乳腺癌。
Breast Cancer Res. 2019 Dec 4;21(1):135. doi: 10.1186/s13058-019-1222-0.
8
Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors.发现并优化杂芳基哌嗪类化合物作为高效和选择性的 PI3Kδ 抑制剂。
Bioorg Med Chem Lett. 2020 Jan 1;30(1):126715. doi: 10.1016/j.bmcl.2019.126715. Epub 2019 Oct 18.
9
PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges.PI3K/AKT/mTOR 通路抑制剂在三阴性乳腺癌中的应用：药物发现及未来挑战的综述
Drug Discov Today. 2019 Nov;24(11):2181-2191. doi: 10.1016/j.drudis.2019.09.001. Epub 2019 Sep 11.
10
Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design.通过构象限制和基于结构的设计发现 3,4,6-三取代哌啶衍生物作为具有口服活性的低 hERG 阻断 Akt 抑制剂。
J Med Chem. 2019 Aug 8;62(15):7264-7288. doi: 10.1021/acs.jmedchem.9b00891. Epub 2019 Jul 24.