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

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 <i>N</i>-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.