Development of UTX-121 and its derivatives as novel matrix metalloproteinase-2/9 inhibitors using celecoxib as a lead compound

Matrix metalloproteinases (MMP)-2/9 are closely associated with cancer malignancy, and it has been considered that the inhibition of these MMPs may be beneficial for enhancing the antitumor and antimetastatic activities of agents. In addition, celecoxib, a COX-2 selective inhibitor, has been reported to have a poor MMPs inhibitory activity, suggesting that it is a very promising drug as an anticancer and antimetastatic agent. We have revealed that UTX-121, which was converted the sulfonamide moiety of celecoxib into a methyl ester, significantly suppressed MT1-MMP-mediated MMP-2 activation and MMP-9 production. Furthermore, UTX-121 also inhibited the migration and invasion of cancer cells. We then searched for compounds with higher MMPs inhibitory activity using a structure-activity relationship (SAR) method based on UTX-121 as a lead compound. Among them, compounds 9c and 10c, in which the methyl moiety of the p-tolyl group in UTX-121 was substituted with F and Cl, showed higher antitumor and MMPs inhibitory activities than UTX-121. These findings suggest that compounds 9c and 10c could be potential lead compounds for the development of potent MMPs inhibitors.

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