Structure-Activity Relationships of UTX-121 Derivatives for the Development of Novel Matrix Metalloproteinase-2/9 Inhibitors.

Abstract

Celecoxib, a nonsteroidal anti-inflammatory drug, has been reported to have antitumor and antimetastatic activities, and it has potential for application in cancer treatments. The expression of matrix metalloproteinase (MMP)-2/9 is strongly correlated with cancer malignancy, and inhibition of these MMPs is believed to be effective in improving the antitumor and antimetastatic effects of drugs. We have previously revealed that UTX-121, which converted the sulfonamide of celecoxib to methyl ester, has more potent MMP-2/9 inhibitory activity than celecoxib. Based on these findings, we identified compounds with improved MMP inhibitory activity through a structure-activity relationship (SAR) study, using UTX-121 as a lead compound. Among them, compounds 9c and 10c, in which the methyl group of the p-tolyl group was substituted for Cl or F, showed significantly higher antitumor activity than UTX-121, and suppressed the expression of MMP-2/9 and activation of pro MMP-2. Our findings suggest that compounds 9c and 10c may be potent lead compounds for the development of more effective antitumor drugs targeting MMP.

• Authors: Hirari Yamahana, Yuki Komiya, Takahisa Takino, Yoshio Endo, Hisatsugu Yamada, Chikako Asada, Yoshihiro Uto
• Journal: Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 69 Issue 10 Pg. 1017-1028 ( 2021) ISSN: 1347-5223 [Electronic] Japan
• PMID: 34602570 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Development
• Drug Screening Assays, Antitumor
• Humans
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Structure-Activity Relationship