Siyuan Liu, Fusheng Wang, Caifang Zhang, Hong Jiang, Chun Liu
{"title":"4-（（3-（四氢- 2h -吡喃-4-基）- 1h -吡唑-4-基）氧）喹啉衍生物作为潜在的肝癌转化生长因子-β 1型受体抑制剂的合成和生物学评价","authors":"Siyuan Liu, Fusheng Wang, Caifang Zhang, Hong Jiang, Chun Liu","doi":"10.1016/j.bioorg.2025.108156","DOIUrl":null,"url":null,"abstract":"<p><p>The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a key role in tumor microenvironment. Small-molecule inhibitors of TGFβR1 provides a prospective approach for the treatment of malignant tumors. In this study, a series of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives were identified as novel, potential TGFβR1 inhibitors. The most potent compound 16w inhibited SMAD2/3 phosphorylation and H22 cell viability with IC<sub>50</sub> values of 12 and 65 nM, respectively. Further, compound 16w exhibited reasonable pharmacokinetic profiles and exhibited significant anti-tumor efficacy in a xenograft model of H22 cells, with TGI of 79.6 %. Additionally, compound 16w also showed a strong synergistic proapoptotic effect in combination with sorafenib, which provided a promising lead for further development of novel anticancer drugs.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"108156"},"PeriodicalIF":4.5000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis and biological evaluation of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives as novel potential transforming growth factor-β type 1 receptor inhibitors for hepatocellular carcinoma.\",\"authors\":\"Siyuan Liu, Fusheng Wang, Caifang Zhang, Hong Jiang, Chun Liu\",\"doi\":\"10.1016/j.bioorg.2025.108156\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a key role in tumor microenvironment. Small-molecule inhibitors of TGFβR1 provides a prospective approach for the treatment of malignant tumors. In this study, a series of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives were identified as novel, potential TGFβR1 inhibitors. The most potent compound 16w inhibited SMAD2/3 phosphorylation and H22 cell viability with IC<sub>50</sub> values of 12 and 65 nM, respectively. Further, compound 16w exhibited reasonable pharmacokinetic profiles and exhibited significant anti-tumor efficacy in a xenograft model of H22 cells, with TGI of 79.6 %. Additionally, compound 16w also showed a strong synergistic proapoptotic effect in combination with sorafenib, which provided a promising lead for further development of novel anticancer drugs.</p>\",\"PeriodicalId\":257,\"journal\":{\"name\":\"Bioorganic Chemistry\",\"volume\":\"155 \",\"pages\":\"108156\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2025-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1016/j.bioorg.2025.108156\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/10 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1016/j.bioorg.2025.108156","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Synthesis and biological evaluation of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives as novel potential transforming growth factor-β type 1 receptor inhibitors for hepatocellular carcinoma.
The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a key role in tumor microenvironment. Small-molecule inhibitors of TGFβR1 provides a prospective approach for the treatment of malignant tumors. In this study, a series of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives were identified as novel, potential TGFβR1 inhibitors. The most potent compound 16w inhibited SMAD2/3 phosphorylation and H22 cell viability with IC50 values of 12 and 65 nM, respectively. Further, compound 16w exhibited reasonable pharmacokinetic profiles and exhibited significant anti-tumor efficacy in a xenograft model of H22 cells, with TGI of 79.6 %. Additionally, compound 16w also showed a strong synergistic proapoptotic effect in combination with sorafenib, which provided a promising lead for further development of novel anticancer drugs.
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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