Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors.

IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL
Pharmaceuticals Pub Date : 2025-02-19 DOI:10.3390/ph18020275
Esraa Mahmoud, Dalia Abdelhamid, Anber F Mohammed, Zainab M Almarhoon, Stefan Bräse, Bahaa G M Youssif, Alaa M Hayallah, Mohamad Abdel-Aziz
{"title":"Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors.","authors":"Esraa Mahmoud, Dalia Abdelhamid, Anber F Mohammed, Zainab M Almarhoon, Stefan Bräse, Bahaa G M Youssif, Alaa M Hayallah, Mohamad Abdel-Aziz","doi":"10.3390/ph18020275","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background/Objectives:</b> New indole/1,2,4-triazole hybrids were synthesized and tested for antiproliferative activity against the NCI 60 cell line as tubulin polymerization inhibitors. <b>Methods:</b> All final compounds, <b>6a</b>-<b>j</b> and <b>7a</b>-<b>j</b> were evaluated at a single concentration of 10 µM against a panel of sixty cancer cell lines. <b>Results:</b> Compounds <b>7a</b>-<b>j</b>, featuring the NO-releasing oxime moiety, exhibited superior anticancer activity to their precursor ketones <b>6a</b>-<b>j</b> across all tested cancer cell lines. Compounds <b>6h</b>, <b>7h</b>, <b>7i</b>, and <b>7j</b> were chosen for five-dose evaluations against a comprehensive array of 60 human tumor cell lines. The data showed that all tested compounds had significant anticancer activity throughout the nine tumor subpanels studied, with selectivity ratios ranging from 0.52 to 2.29 at the GI<sub>50</sub> level. Compounds <b>7h</b> and <b>7j</b> showed substantial anticancer effectiveness against most cell lines across nine subpanels, with GI<sub>50</sub> values ranging from 1.85 to 5.76 µM and 2.45 to 5.23 µM. Compounds <b>6h</b>, <b>7h</b>, <b>7i</b>, and <b>7j</b> were assessed for their inhibitory effects on tubulin polymerization. <b>Conclusions:</b> The results showed that compound <b>7i</b>, an oxime-based derivative, was the most effective at blocking tubulin, with an IC<sub>50</sub> value of 3.03 ± 0.11 µM. This was compared to the standard drug CA-4, which had an IC<sub>50</sub> value of 8.33 ± 0.29 µM. Additionally, cell cycle analysis and apoptosis assays were performed for compound <b>7i</b>. Molecular computational investigations have been performed to examine the binding mode of the most effective compounds to the target enzyme.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 2","pages":""},"PeriodicalIF":4.3000,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11859928/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceuticals","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/ph18020275","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

Abstract

Background/Objectives: New indole/1,2,4-triazole hybrids were synthesized and tested for antiproliferative activity against the NCI 60 cell line as tubulin polymerization inhibitors. Methods: All final compounds, 6a-j and 7a-j were evaluated at a single concentration of 10 µM against a panel of sixty cancer cell lines. Results: Compounds 7a-j, featuring the NO-releasing oxime moiety, exhibited superior anticancer activity to their precursor ketones 6a-j across all tested cancer cell lines. Compounds 6h, 7h, 7i, and 7j were chosen for five-dose evaluations against a comprehensive array of 60 human tumor cell lines. The data showed that all tested compounds had significant anticancer activity throughout the nine tumor subpanels studied, with selectivity ratios ranging from 0.52 to 2.29 at the GI50 level. Compounds 7h and 7j showed substantial anticancer effectiveness against most cell lines across nine subpanels, with GI50 values ranging from 1.85 to 5.76 µM and 2.45 to 5.23 µM. Compounds 6h, 7h, 7i, and 7j were assessed for their inhibitory effects on tubulin polymerization. Conclusions: The results showed that compound 7i, an oxime-based derivative, was the most effective at blocking tubulin, with an IC50 value of 3.03 ± 0.11 µM. This was compared to the standard drug CA-4, which had an IC50 value of 8.33 ± 0.29 µM. Additionally, cell cycle analysis and apoptosis assays were performed for compound 7i. Molecular computational investigations have been performed to examine the binding mode of the most effective compounds to the target enzyme.

求助全文
约1分钟内获得全文 求助全文
来源期刊
Pharmaceuticals
Pharmaceuticals Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
6.10
自引率
4.30%
发文量
1332
审稿时长
6 weeks
期刊介绍: Pharmaceuticals (ISSN 1424-8247) is an international scientific journal of medicinal chemistry and related drug sciences.Our aim is to publish updated reviews as well as research articles with comprehensive theoretical and experimental details. Short communications are also accepted; therefore, there is no restriction on the maximum length of the papers.
×
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:481959085
Book学术官方微信