Mohamed A Mahmoud, Anber F Mohammed, Ola I A Salem, Tahani Mazyad Almutairi, Stefan Bräse, Bahaa G M Youssif
{"title":"新型 1,2,3-三唑/1,2,4-恶二唑混合物作为表皮生长因子受体/表皮生长因子受体-2 双重抑制剂的设计、合成和凋亡抗增殖作用。","authors":"Mohamed A Mahmoud, Anber F Mohammed, Ola I A Salem, Tahani Mazyad Almutairi, Stefan Bräse, Bahaa G M Youssif","doi":"10.1080/14756366.2024.2305856","DOIUrl":null,"url":null,"abstract":"<p><p>A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (<b>7a</b>-<b>o</b>) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds <b>7a</b>-<b>o</b> were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI<sub>50</sub> values ranging from 28 to 104 nM, compared to Erlotinib (GI<sub>50</sub> = 33 nM), and compounds <b>7i</b>-<b>m</b> were the most potent. Compounds <b>7h</b>, <b>7i</b>, <b>7j</b>, <b>7k</b>, and <b>7l</b> were evaluated as dual EGFR/VEGFR-2 inhibitors. These <i>in vitro</i> experiments demonstrated that compounds <b>7j</b>, <b>7k</b>, and <b>7l</b> are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds <b>7j</b>, <b>7k</b>, and <b>7l</b> were evaluated for their apoptotic potential activity, where findings indicated that compounds <b>7j</b>, <b>7k,</b> and <b>7l</b> promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2305856"},"PeriodicalIF":5.6000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10854447/pdf/","citationCount":"0","resultStr":"{\"title\":\"Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors.\",\"authors\":\"Mohamed A Mahmoud, Anber F Mohammed, Ola I A Salem, Tahani Mazyad Almutairi, Stefan Bräse, Bahaa G M Youssif\",\"doi\":\"10.1080/14756366.2024.2305856\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (<b>7a</b>-<b>o</b>) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds <b>7a</b>-<b>o</b> were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI<sub>50</sub> values ranging from 28 to 104 nM, compared to Erlotinib (GI<sub>50</sub> = 33 nM), and compounds <b>7i</b>-<b>m</b> were the most potent. Compounds <b>7h</b>, <b>7i</b>, <b>7j</b>, <b>7k</b>, and <b>7l</b> were evaluated as dual EGFR/VEGFR-2 inhibitors. These <i>in vitro</i> experiments demonstrated that compounds <b>7j</b>, <b>7k</b>, and <b>7l</b> are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds <b>7j</b>, <b>7k</b>, and <b>7l</b> were evaluated for their apoptotic potential activity, where findings indicated that compounds <b>7j</b>, <b>7k,</b> and <b>7l</b> promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"39 1\",\"pages\":\"2305856\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10854447/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2024.2305856\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/2/7 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2024.2305856","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/7 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors.
A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.
期刊介绍:
Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents.
Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research.
The journal’s focus includes current developments in:
Enzymology;
Cell biology;
Chemical biology;
Microbiology;
Physiology;
Pharmacology leading to drug design;
Molecular recognition processes;
Distribution and metabolism of biologically active compounds.