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用于抗光老化的基于异羟肟酸酯的基质金属蛋白酶-2抑制剂的设计与合成

Design and Synthesis of Hydroxamate-Based Matrix Metalloproteinase-2 Inhibitors for Anti-Photoaging.

作者信息

Lee Jin Young, Jang Geunhyuk, Joo Yung Hyup, Choi Joonho, Lee Dong-Woo, Yoo Jae Won

机构信息

Amorepacific Research and Innovation Center, Yongin, Gyeonggi-do 17074, Republic of Korea.

Graduate Program in Biomaterials Science & Engineering, Yonsei University, Seoul 03722, Republic of Korea.

出版信息

J Microbiol Biotechnol. 2025 Feb 10;35:e2412027. doi: 10.4014/jmb.2412.12027.

DOI:10.4014/jmb.2412.12027
PMID:39947701
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11876007/
Abstract

Matrix metalloproteinases-2 (MMP-2) is crucial for collagen degradation at the dermal-epidermal junction, contributing to skin aging and photoaging. This study presents a series of hydroxamate-based inhibitors selectively targeting MMP-2. Through structure-activity relationship analysis, we systematically modified the -arylsulfonyl group and amino acid backbone to enhance MMP-2 selectivity. Compounds 1ad, 1af, and 4an showed strong MMP-2 inhibition, with 1ad demonstrating nanomolar-level selectivity. Zymogram assays revealed 30-60% MMP-2 activity reduction, while gene expression analysis confirmed post-transcriptional inhibition. These hydroxamate-based inhibitors are promising candidates for anti-photoaging applications, combining potent MMP-2 inhibition with simplified synthesis, supporting their potential for large-scale cosmetic formulations aimed at improving skin firmness and reducing wrinkles.

摘要

基质金属蛋白酶-2（MMP-2）对于真皮-表皮交界处的胶原蛋白降解至关重要，会导致皮肤老化和光老化。本研究展示了一系列选择性靶向MMP-2的基于异羟肟酸的抑制剂。通过构效关系分析，我们系统地修饰了芳基磺酰基和氨基酸主链以提高MMP-2的选择性。化合物1ad、1af和4an表现出强烈的MMP-2抑制作用，其中1ad显示出纳摩尔级的选择性。酶谱分析显示MMP-2活性降低了30-60%，而基因表达分析证实了转录后抑制作用。这些基于异羟肟酸的抑制剂是抗光老化应用的有前景的候选物，它们结合了强效的MMP-2抑制作用和简化的合成方法，支持了它们用于旨在改善皮肤紧致度和减少皱纹的大规模化妆品配方的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/df564ffd5780/jmb-35-e2412027-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/456bd9a1f51c/jmb-35-e2412027-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/01b9e479ddd9/jmb-35-e2412027-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/0f40c4f6d322/jmb-35-e2412027-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/7b19f95454b7/jmb-35-e2412027-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/df564ffd5780/jmb-35-e2412027-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/456bd9a1f51c/jmb-35-e2412027-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/01b9e479ddd9/jmb-35-e2412027-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/0f40c4f6d322/jmb-35-e2412027-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/7b19f95454b7/jmb-35-e2412027-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bd3/11876007/df564ffd5780/jmb-35-e2412027-f5.jpg

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本文引用的文献

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Overview of popular cosmeceuticals in dermatology.皮肤科常用药妆概述。
Skin Health Dis. 2024 Feb 7;4(2):e340. doi: 10.1002/ski2.340. eCollection 2024 Apr.
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UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner.中波紫外线介导的 DNA 损伤诱导基质金属蛋白酶以 AhR 和 SP1 依赖的方式促进光老化。
JCI Insight. 2022 May 9;7(9):e156344. doi: 10.1172/jci.insight.156344.
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The Human Epidermal Basement Membrane: A Shaped and Cell Instructive Platform That Aging Slowly Alters.人类表皮基底膜：一种形态和细胞指令性平台，随年龄缓慢改变。
Biomolecules. 2020 Nov 27;10(12):1607. doi: 10.3390/biom10121607.
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AMDock: a versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4.AMDock：一个通用的图形工具，用于辅助 Autodock Vina 和 Autodock4 进行分子对接。
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The GTEx Consortium atlas of genetic regulatory effects across human tissues.GTEx 联盟人类组织遗传调控效应图谱
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Challenges in Matrix Metalloproteinases Inhibition.基质金属蛋白酶抑制的挑战。
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Understanding the variability of the S1' pocket to improve matrix metalloproteinase inhibitor selectivity profiles.了解 S1' 口袋的变异性，以改善基质金属蛋白酶抑制剂的选择性特征。
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