Combining carbonic anhydrase and thioredoxin reductase inhibitory motifs within a single molecule dramatically increases its cytotoxicity

Abstract

A hypothesis that simultaneous targeting cancer-related carbonic anhydrase hCA IX and hCA XII isoforms (whose overexpression is a cancer cell’s defence mechanism against hypoxia) along with thioredoxin reductase (overexpressed in cancers as a defence against oxidative stress) may lead to synergistic antiproliferative effects was confirmed by testing combinations of the two inhibitor classes against pancreatic cancer cells (PANC-1). Combining both pharmacophoric motifs within one molecule led to a sharp increase of cytotoxicity. This preliminary observation sets the ground for a fundamentally new approach to anticancer agent design.

Graphical Abstract

Keywords:

• Anticancer agents
• carbonic anhydrase inhibition
• thioredoxin reductase inhibition
• synergistic effect
• dual pharmacophores
• Michael acceptors
• zinc-binding group
• hypoxia
• oxidative stress
• cancer cell defence mechanisms

Acknowledgements

We thank the Research Centre for Magnetic Resonance, the Centre for Chemical Analysis and Materials Research of Saint Petersburg State University Research Park for obtaining the analytical data.

Disclosure statement

The authors declare no competing financial interest.

Additional information

Funding

This work was supported by the Russian Foundation for Basic Research (project grant 19–33-90017).