{"title":"含有 5-芳基-4-噻唑啉酮的四氢咔唑作为潜在的抗白血病和抗淋巴瘤靶向酪氨酸激酶和管蛋白聚合酶：设计、合成、结构、生物学和分子对接研究","authors":"","doi":"10.1016/j.bioorg.2024.107817","DOIUrl":null,"url":null,"abstract":"<div><p>Finding effective and selective anticancer agents is a top medical priority due to high clinical treatment demand. However, current anticancer agents have serious side effects and resistance development remains a big concern. This creates an urgent need for new multitarget drugs that could solve these problems. Tetrahydrocarbazoles and 5-arylidene-4-thiazolinones have always attracted researchers for their multifaced anticancer activities and the possibility to be easily derivatized. Thereby, herein we report the combination of the two scaffolds to provide compounds <strong>9a</strong>-<strong>j</strong> and <strong>10a</strong>-<strong>j</strong> that were fully characterized and their tautomeric form was confirmed by crystal structure. <strong>9a</strong>-<strong>j</strong> and <strong>10a</strong>-<strong>j</strong> were<!--> <!-->assessed<!--> <!-->for <em>in<!--> <!-->vitro</em> antiproliferative activity<!--> <!-->using SRB assay against a panel of seven human cancer cell lines with doxorubicin as the standard. The results revealed that the cell lines derived from leukemia (Jurkat) and lymphoma (U937) are the most sensitive. Compounds <strong>9d</strong>, <strong>10e</strong>, <strong>10g</strong>, and <strong>10f</strong> revealed the highest potency (IC<sub>50</sub> = 3.11–11.89 μM) with much lower effects on normal lymphocytes cell line (IC<sub>50</sub> > 50 µM). The results show that modifications at 6th position of the THC and the nature of the substituent at the arylidene moiety affect the activity. To exploit the mode of action, <strong>9d</strong>, <strong>10e, 10f</strong>, and <strong>10g</strong> were evaluated as VEGFR-2 and EGFR inhibitors. <strong>10e</strong> is the most potent (IC<sub>50</sub> 0.26 and 0.14 μM) against both enzymes. It also induced G0-G1-phase cell cycle arrest and apoptosis. While <strong>10g</strong> exhibited higher potency (IC<sub>50</sub> 9.95 μM) than vincristine (IC<sub>50</sub> 15.63 μM) against tubulin. A molecular docking study was carried out to understand the interactions between <strong>10e</strong>, <strong>10g</strong> and their targets. This study reveals <strong>10e</strong> and <strong>10g</strong> as possible candidates for developing multitarget anticancer agents against leukemia and lymphoma.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tetrahydrocarbazoles incorporating 5-arylidene-4-thiazolinones as potential antileukemia and antilymphoma targeting tyrosine kinase and tubulin polymerase enzymes: Design, synthesis, structural, biological and molecular docking studies\",\"authors\":\"\",\"doi\":\"10.1016/j.bioorg.2024.107817\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Finding effective and selective anticancer agents is a top medical priority due to high clinical treatment demand. However, current anticancer agents have serious side effects and resistance development remains a big concern. This creates an urgent need for new multitarget drugs that could solve these problems. Tetrahydrocarbazoles and 5-arylidene-4-thiazolinones have always attracted researchers for their multifaced anticancer activities and the possibility to be easily derivatized. Thereby, herein we report the combination of the two scaffolds to provide compounds <strong>9a</strong>-<strong>j</strong> and <strong>10a</strong>-<strong>j</strong> that were fully characterized and their tautomeric form was confirmed by crystal structure. <strong>9a</strong>-<strong>j</strong> and <strong>10a</strong>-<strong>j</strong> were<!--> <!-->assessed<!--> <!-->for <em>in<!--> <!-->vitro</em> antiproliferative activity<!--> <!-->using SRB assay against a panel of seven human cancer cell lines with doxorubicin as the standard. The results revealed that the cell lines derived from leukemia (Jurkat) and lymphoma (U937) are the most sensitive. Compounds <strong>9d</strong>, <strong>10e</strong>, <strong>10g</strong>, and <strong>10f</strong> revealed the highest potency (IC<sub>50</sub> = 3.11–11.89 μM) with much lower effects on normal lymphocytes cell line (IC<sub>50</sub> > 50 µM). The results show that modifications at 6th position of the THC and the nature of the substituent at the arylidene moiety affect the activity. To exploit the mode of action, <strong>9d</strong>, <strong>10e, 10f</strong>, and <strong>10g</strong> were evaluated as VEGFR-2 and EGFR inhibitors. <strong>10e</strong> is the most potent (IC<sub>50</sub> 0.26 and 0.14 μM) against both enzymes. It also induced G0-G1-phase cell cycle arrest and apoptosis. While <strong>10g</strong> exhibited higher potency (IC<sub>50</sub> 9.95 μM) than vincristine (IC<sub>50</sub> 15.63 μM) against tubulin. A molecular docking study was carried out to understand the interactions between <strong>10e</strong>, <strong>10g</strong> and their targets. This study reveals <strong>10e</strong> and <strong>10g</strong> as possible candidates for developing multitarget anticancer agents against leukemia and lymphoma.</p></div>\",\"PeriodicalId\":257,\"journal\":{\"name\":\"Bioorganic Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0045206824007223\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824007223","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Tetrahydrocarbazoles incorporating 5-arylidene-4-thiazolinones as potential antileukemia and antilymphoma targeting tyrosine kinase and tubulin polymerase enzymes: Design, synthesis, structural, biological and molecular docking studies
Finding effective and selective anticancer agents is a top medical priority due to high clinical treatment demand. However, current anticancer agents have serious side effects and resistance development remains a big concern. This creates an urgent need for new multitarget drugs that could solve these problems. Tetrahydrocarbazoles and 5-arylidene-4-thiazolinones have always attracted researchers for their multifaced anticancer activities and the possibility to be easily derivatized. Thereby, herein we report the combination of the two scaffolds to provide compounds 9a-j and 10a-j that were fully characterized and their tautomeric form was confirmed by crystal structure. 9a-j and 10a-j were assessed for in vitro antiproliferative activity using SRB assay against a panel of seven human cancer cell lines with doxorubicin as the standard. The results revealed that the cell lines derived from leukemia (Jurkat) and lymphoma (U937) are the most sensitive. Compounds 9d, 10e, 10g, and 10f revealed the highest potency (IC50 = 3.11–11.89 μM) with much lower effects on normal lymphocytes cell line (IC50 > 50 µM). The results show that modifications at 6th position of the THC and the nature of the substituent at the arylidene moiety affect the activity. To exploit the mode of action, 9d, 10e, 10f, and 10g were evaluated as VEGFR-2 and EGFR inhibitors. 10e is the most potent (IC50 0.26 and 0.14 μM) against both enzymes. It also induced G0-G1-phase cell cycle arrest and apoptosis. While 10g exhibited higher potency (IC50 9.95 μM) than vincristine (IC50 15.63 μM) against tubulin. A molecular docking study was carried out to understand the interactions between 10e, 10g and their targets. This study reveals 10e and 10g as possible candidates for developing multitarget anticancer agents against leukemia and lymphoma.
期刊介绍：
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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