Effect of Sulfonamide Group Modification on Celecoxib: Molecular Features of Matrix Metalloproteinase Interactive UTX-121 Derivative

Matrix metalloproteinases (MMPs) are important for extracellular matrix (ECM) degradation with MMP inhibition possibly leading to new antitumor therapies. To examine this possibility, UTX-121, in which the celecoxib sulfonamide was replaced with a methyl ester, was designed to examine the influence of UTX-121 derivatives on MMPs. HT-1080 cells were incubated with UTX-121 derivatives over 48 h, and antitumor activities (IC50) were examined using WST-8 assay. The inhibitory effect of UTX-121 derivatives on MMPs in HT-1080 cells was examined using gelatin zymography. Conformational analyses of UTX-121 derivatives were performed using CAChe-Conflex. The interaction of UTX-121 derivatives with MMPs was analyzed using Molegro Virtual Docker. UTX-121 derivative a2 exhibited enhanced antitumor activity compared to UTX-121. Additionally, derivative a2 demonstrated stronger inhibitory effects on MMP-2, as indicated by reduced band intensity in gelatin zymography, compared to UTX-121. Molecular docking simulations revealed that a2 formed a hydrogen bond with the Tyr366 residue of MMP-2 via the oxygen atom of its methoxy group, supporting its enhanced interaction and inhibitory potency. UTX-121 derivative a2 showed improved MMP-2 inhibitory activity through specific hydrogen bonding interactions and holds promise as a lead compound for the development of novel MMP-2-targeted anticancer agents.