Multitargeting application of proline-derived peptidomimetics addressing cancer-related human matrix metalloproteinase 9 and carbonic anhydrase II

A series of D-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhy-drases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of D-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of D-proline peptidomimetics were found to act as dual inhibitors of human carbonic anhydrases and human gelatinases, potentially offering a new treatment approach for gastric cancer.