Dual targeting of cancer-related human matrix metalloproteinases and carbonic anhydrases by chiral N-(biarylsulfonyl)-phosphonic acids

Abstract

A series of nanomolar phosphonate matrix metalloproteinase (MPP) inhibitors was tested for inhibitory activity against a panel of selected human carbonic anhydrase (CA, EC 4.2.1.1) isozymes, covering the cancer-associated CA IX and XII. None of the reported sulfonyl and sulfonylamino-derivatives sensitively affected the catalytic activity of the cytosolic isoforms CA I and II, which are considered off-target isoforms in view of their physiological role. The most active inhibitors were in the series of chiral N-(sulfonyl)phosphovaline derivatives, which showed good to excellent inhibitory activity over target CAs, with compound 15 presenting the best isoform-selectivity toward CA IX. We suggest here that the phosphonates have the potential as dual inhibitors of MMPs and CAs, both involved in tumor formation, invasion and metastasis.

Keywords:

• Carbonic anhydrases
• matrix metalloproteinases
• phosphonic acids
• sulfonamides
• zinc-binding group

Disclosure statement

The authors declare no conflict of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by G. d’Annunzio” University of Chieti-Pescara, (MIUR 2016, ex 60% Grant).