Effect of Tolyl Modification on Celecoxib Related Structure: Molecular Features of MMP-interacting UTX-121 Derivatives.

BACKGROUND/AIM: Matrix metalloproteinases (MMPs) are important enzymes in extracellular matrix degradation. Several cancer types overexpress MMPs, indicating that MMP inhibition may be a viable approach to induce antitumor activity. To explore this, we designed UTX-121, a molecule in which the sulfonamide group of celecoxib is replaced with a methyl ester group. From this structure, a range of UTX-121 derivatives were developed in which the tolyl moiety was modified. The MMP inhibitory effects of these derivatives were then examined.

MATERIALS AND

METHODS

HT-1080 cells were incubated with UTX-121 derivatives for 48 h, and antitumor activities (IC50) were examined using the WST-8 assay. MMP inhibition in HT-1080 cells by UTX-121 derivatives was evaluated by gelatin zymography. UTX-121 derivative conformational analysis was performed using CAChe-Conflex (Fujitsu Inc., Tokyo, Japan). MMP interactions with UTX-121 derivatives were analyzed by Molegro Virtual Docker (CLC bio., Aarhus, Denmark).

RESULTS

The antitumor activities of UTX-121 derivatives b1-b3, b8, and b11 were greater than those of UTX-121. Derivatives b1-b3, b8, and b11 yielded greater MMP-9 inhibition than UTX-121. Derivatives b1-b3 also inhibited MMP-2. Modelling indicated that derivatives b1-b3, b8, and b11 bound to the MMP-9 enzyme, mediated by a hydrogen bond. Derivatives b1-b3 also bound to MMP-2.

CONCLUSION

Derivatives b1-b3, which regulate both MMP-9 and MMP-2 function, appear to have structural features associated with broader MMP interactions. In contrast, MMP-9-specific probes may be developed using the structural features of derivatives b8 and b11.