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Effect of Sulfonamide Group Modification on Celecoxib: Molecular Features of Matrix Metalloproteinase Interactive
Kazuto Ohkura1, Atsushi Tabata2, Yoshihiro Uto2
1Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan; kohkura@suzuka-u.ac.jp.
Background/Aim:
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.
Materials And Methods:
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.
Results:
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.
Conclusion:
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.
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