Discovery and evaluation of novel Benzohydroxamic acid-indole derivatives as dual inhibitors of ADAM17 and HDAC2 with antitumor activity

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-02-28 DOI:10.1016/j.bioorg.2025.108308

Xiaoxuan Song , Xin Tong , Kaisi Yang , Yiming Qi , Wenwu Liu , Yuzhu Sun , Chengkang Wang , Fanghua Xun , Ziyi Wang , Muxuan Jiang , Yingshi Zhang , Tianshu Ren , Di Chen , Shanbo Hou , Aigang Song , Huiyuan Gao , Qingchun Zhao

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Abstract

Hepatocellular carcinoma (HCC) has garnered significant attention from researchers due to its high recurrence rate and invasive characteristics. The design of drugs with dual-target combined effects represents a promising strategy in cancer treatment. Our observations suggest that ADAM17 and HDAC may inhibit the unfavorable prognostic signaling pathway Notch1 in HCC through distinct mechanisms, thereby suppressing tumor cell proliferation and metastasis. Consequently, this study utilized the ADAM17 inhibitor ZLDI-8 as a lead compound and developed a series of dual ADAM17/HDAC2 inhibitors by integrating strategies such as backbone leaping and pharmacophore fusion. We assessed the anti-hepatocellular carcinoma activity of these compounds, focusing on their anti-proliferative, pro-apoptotic, and anti-metastatic properties. Notably, ZSNI-21 effectively inhibited the proliferation of Bel-7402 cells and demonstrated significant anti-metastatic capabilities against HCC-LM3 cells, with its targeting confirmed. Additionally, its in vivo safety was validated. To date, there have been no reports on dual ADAM17/HDAC2 inhibitors, marking this as a novel endeavor.

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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.