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.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2025-02-01 Epub Date: 2025-01-10 DOI:10.1016/j.bioorg.2025.108156

Siyuan Liu, Fusheng Wang, Caifang Zhang, Hong Jiang, Chun Liu

引用次数: 0

Abstract

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.

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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

转化生长因子β (TGF-β) 1型受体（ALK5）在肿瘤微环境中起关键作用。TGFβR1的小分子抑制剂为恶性肿瘤的治疗提供了一条有前景的途径。在本研究中，一系列4-（（3-（四氢- 2h -吡喃-4-基）- 1h -吡唑-4-基）氧）喹啉衍生物被鉴定为新的、潜在的tgf - β r1抑制剂。最有效的化合物16w抑制SMAD2/3磷酸化和H22细胞活力，IC50值分别为12 nM和65 nM。此外，化合物16w具有合理的药代动力学特征，在H22细胞异种移植模型中表现出显著的抗肿瘤功效，TGI为79.6%。此外，化合物16w与索拉非尼联合也显示出较强的协同促凋亡作用，为进一步开发新型抗癌药物提供了有希望的先导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

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.