新型 3-萘基噻吩衍生物作为强效 SIRT2 抑制剂用于治疗心肌纤维化的设计、合成和生物学评价。

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zhuo Zhang, Chao Ma, Xiong Gao, Chuncheng Wang, Yanchun Li, Chen Yang, Enlong Ma, Maosheng Cheng
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引用次数: 0

摘要

本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design, synthesis, and biological evaluation of novel 3-naphthylthiophene derivatives as potent SIRT2 inhibitors for the treatment of myocardial fibrosis.

SIRT2 (sirtuin2) is a NAD+-dependent deacetylase implicated in fibrosis and inflammation of the liver, kidney, and heart. In this study, we designed and synthesized a series of 3-naphthylthiophene derivatives and evaluated their inhibitory activity against the SIRT2 enzyme. Among them, Z18 demonstrated outstanding SIRT2 inhibitory activity and selectivity. It significantly inhibited both the proliferation of cardiac fibroblasts (CFs) and the activity and expression of SIRT2 in CFs. Moreover, compound Z18 effectively suppressed TGF-β1-induced increases in α-SMA and CoL-1A1 protein expression, as well as hydroxyproline levels. Pharmacological mechanism tests demonstrated that Z18 inhibited SIRT2, thereby suppressing the TGF-β1-induced autocrine production of TGF-β1 and the phosphorylation of Smad2/3 in CFs. In MTT assays, Z18 exhibited a significant inhibitory effect on the proliferation of CFs induced by TGF-β1. In vivo, Z18 effectively ameliorated TAC- and ISO-induced declines in cardiac function, histopathological morphological changes, and collagen deposition. It also inhibited SIRT2 activity and reduced the expression of α-SMA and p-Smad2/3. In hepatorenal toxicity assays, Z18 exhibited an excellent safety profile. These results support the further development of the selective SIRT2 inhibitor Z18 as a potential lead compound for the treatment of myocardial fibrosis.

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来源期刊
Bioorganic Chemistry
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.
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