具有潜在抗乳腺活性的新型1,3,4-噻二唑类双B-Raf/VEGFR-2抑制剂:设计、合成、体外和计算机评价

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Walid E Elgammal, Hazem Elkady, Hazem A Mahdy, Bshra A Alsfouk, Dalal Z Husein, Fatma G Amin, Abdelrahman A Abuelkhir, Eslam B Elkaeed, Ahmed M Metwaly, Ibrahim H Eissa
{"title":"具有潜在抗乳腺活性的新型1,3,4-噻二唑类双B-Raf/VEGFR-2抑制剂:设计、合成、体外和计算机评价","authors":"Walid E Elgammal, Hazem Elkady, Hazem A Mahdy, Bshra A Alsfouk, Dalal Z Husein, Fatma G Amin, Abdelrahman A Abuelkhir, Eslam B Elkaeed, Ahmed M Metwaly, Ibrahim H Eissa","doi":"10.1002/ardp.70097","DOIUrl":null,"url":null,"abstract":"<p><p>This study reports the design, synthesis, and biological evaluation of a novel series of 1,3,4-thiadiazole-based derivatives as dual B-Raf and VEGFR-2 kinase inhibitors with potential anticancer activity. Among the synthesized compounds, 7b emerged as the most potent candidate, exhibiting strong cytotoxicity against the MDA-MB-231 and MCF-7 breast cancer cell lines (IC₅₀ = 9.66 and 15.83 µM, respectively), with minimal toxicity toward normal WI-38 and WISH cells, reflected by favorable selectivity indices. Compound 7b, featuring a unique structural assembly of a 2,3-dihydro-1,3,4-thiadiazole core, a para-methoxyphenyl group, and a sulfonamide-linked methylpiperidine moiety, exhibited superior dual-inhibitory activity. It showed IC₅₀ values of 0.75 µM for B-Raf and 58.13 nM for VEGFR-2. Flow cytometry and gene expression analysis revealed that 7b induces G1-phase cell-cycle arrest and promotes apoptosis through the upregulation of BAX, caspases-8/9, and downregulation of Bcl-2. Compound 7b also inhibited cell migration in wound-healing assays. Structure-activity relationship (SAR) analysis indicated that para-substituted electron-donating groups enhanced cytotoxic potency. Molecular docking and molecular dynamics simulations confirmed the stable binding of 7b to the kinase active sites, supported by favorable Glide scores (-25.47 kcal/mol for VEGFR-2 and -31.64 kcal/mol) and MM-GBSA (molecular mechanics with generalized Born and surface area solvation) binding energies. Density functional theory (DFT) calculations further validated the compound's electronic stability and reactivity. These integrated findings suggest that compound 7b is a promising lead for further development as a selective dual kinase inhibitor for breast cancer therapy.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":"e70097"},"PeriodicalIF":3.6000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"New 1,3,4-Thiadiazole-Based Dual B-Raf/VEGFR-2 Inhibitors With Potential Anti-Breast Activity: Design, Synthesis, In Vitro and In Silico Evaluations.\",\"authors\":\"Walid E Elgammal, Hazem Elkady, Hazem A Mahdy, Bshra A Alsfouk, Dalal Z Husein, Fatma G Amin, Abdelrahman A Abuelkhir, Eslam B Elkaeed, Ahmed M Metwaly, Ibrahim H Eissa\",\"doi\":\"10.1002/ardp.70097\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>This study reports the design, synthesis, and biological evaluation of a novel series of 1,3,4-thiadiazole-based derivatives as dual B-Raf and VEGFR-2 kinase inhibitors with potential anticancer activity. Among the synthesized compounds, 7b emerged as the most potent candidate, exhibiting strong cytotoxicity against the MDA-MB-231 and MCF-7 breast cancer cell lines (IC₅₀ = 9.66 and 15.83 µM, respectively), with minimal toxicity toward normal WI-38 and WISH cells, reflected by favorable selectivity indices. Compound 7b, featuring a unique structural assembly of a 2,3-dihydro-1,3,4-thiadiazole core, a para-methoxyphenyl group, and a sulfonamide-linked methylpiperidine moiety, exhibited superior dual-inhibitory activity. It showed IC₅₀ values of 0.75 µM for B-Raf and 58.13 nM for VEGFR-2. Flow cytometry and gene expression analysis revealed that 7b induces G1-phase cell-cycle arrest and promotes apoptosis through the upregulation of BAX, caspases-8/9, and downregulation of Bcl-2. Compound 7b also inhibited cell migration in wound-healing assays. Structure-activity relationship (SAR) analysis indicated that para-substituted electron-donating groups enhanced cytotoxic potency. Molecular docking and molecular dynamics simulations confirmed the stable binding of 7b to the kinase active sites, supported by favorable Glide scores (-25.47 kcal/mol for VEGFR-2 and -31.64 kcal/mol) and MM-GBSA (molecular mechanics with generalized Born and surface area solvation) binding energies. Density functional theory (DFT) calculations further validated the compound's electronic stability and reactivity. These integrated findings suggest that compound 7b is a promising lead for further development as a selective dual kinase inhibitor for breast cancer therapy.</p>\",\"PeriodicalId\":128,\"journal\":{\"name\":\"Archiv der Pharmazie\",\"volume\":\"358 9\",\"pages\":\"e70097\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archiv der Pharmazie\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/ardp.70097\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archiv der Pharmazie","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ardp.70097","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

摘要

本研究报道了一系列新的1,3,4-噻二唑衍生物的设计、合成和生物学评价,这些衍生物作为具有潜在抗癌活性的B-Raf和VEGFR-2激酶抑制剂。在所合成的化合物中,7b成为最有效的候选者,对乳腺癌细胞系da - mb -231和MCF-7 (IC₅₀分别= 9.66和15.83µM)表现出很强的细胞毒性,对正常WI-38和WISH细胞的毒性最小,这反映在良好的选择性指数上。化合物7b具有2,3-二氢-1,3,4-噻二唑核、对甲氧基苯基和磺酰胺连接的甲基哌啶部分的独特结构组装,具有优异的双抑制活性。它显示B-Raf的IC₅0值为0.75µM, VEGFR-2的IC₅0值为58.13 nM。流式细胞术和基因表达分析显示,7b通过上调BAX、caspase -8/9和下调Bcl-2诱导g1期细胞周期阻滞,促进细胞凋亡。在创面愈合实验中,化合物7b还能抑制细胞迁移。构效关系(SAR)分析表明,对取代的给电子基团增强了细胞毒性。分子对接和分子动力学模拟证实了7b与激酶活性位点的稳定结合,并得到了良好的Glide分数(VEGFR-2为-25.47 kcal/mol和-31.64 kcal/mol)和MM-GBSA(具有广义Born和表面积溶剂化的分子力学)结合能的支持。密度泛函理论(DFT)计算进一步验证了化合物的电子稳定性和反应性。这些综合研究结果表明,化合物7b作为一种选择性双激酶抑制剂,有望进一步开发用于乳腺癌治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
New 1,3,4-Thiadiazole-Based Dual B-Raf/VEGFR-2 Inhibitors With Potential Anti-Breast Activity: Design, Synthesis, In Vitro and In Silico Evaluations.

This study reports the design, synthesis, and biological evaluation of a novel series of 1,3,4-thiadiazole-based derivatives as dual B-Raf and VEGFR-2 kinase inhibitors with potential anticancer activity. Among the synthesized compounds, 7b emerged as the most potent candidate, exhibiting strong cytotoxicity against the MDA-MB-231 and MCF-7 breast cancer cell lines (IC₅₀ = 9.66 and 15.83 µM, respectively), with minimal toxicity toward normal WI-38 and WISH cells, reflected by favorable selectivity indices. Compound 7b, featuring a unique structural assembly of a 2,3-dihydro-1,3,4-thiadiazole core, a para-methoxyphenyl group, and a sulfonamide-linked methylpiperidine moiety, exhibited superior dual-inhibitory activity. It showed IC₅₀ values of 0.75 µM for B-Raf and 58.13 nM for VEGFR-2. Flow cytometry and gene expression analysis revealed that 7b induces G1-phase cell-cycle arrest and promotes apoptosis through the upregulation of BAX, caspases-8/9, and downregulation of Bcl-2. Compound 7b also inhibited cell migration in wound-healing assays. Structure-activity relationship (SAR) analysis indicated that para-substituted electron-donating groups enhanced cytotoxic potency. Molecular docking and molecular dynamics simulations confirmed the stable binding of 7b to the kinase active sites, supported by favorable Glide scores (-25.47 kcal/mol for VEGFR-2 and -31.64 kcal/mol) and MM-GBSA (molecular mechanics with generalized Born and surface area solvation) binding energies. Density functional theory (DFT) calculations further validated the compound's electronic stability and reactivity. These integrated findings suggest that compound 7b is a promising lead for further development as a selective dual kinase inhibitor for breast cancer therapy.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信