Synthesis of an acridine orange sulfonamide derivative with potent carbonic anhydrase IX inhibitory action

Abstract

Acridine orange (AO) a fluorescent cationic dye used for the management of human musculoskeletal sarcomas, due to its strong tumoricidal action and accumulation in the acidic environment typical of hypoxic tumors, was used for the preparation of a primary sulfonamide derivative. The rationale behind the drug design is the fact that hypoxic, acidic tumors overexpress carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX, which is involved in pH regulation, proliferation, cell migration and invasion, and this enzyme is strongly inhibited by primary sulfonamides. The AO-sulfonamide derivative was indeed a potent, low nanomolar CA IX inhibitor whereas its inhibition of the cytosolic isoforms CA I and II was in the micromolar range. A second transmembrane, tumor-associated isoform, CA XII, was also effectively inhibited by the AO-sulfonamide derivative, making this compound an interesting theranostic agent for the management of hypoxic tumors.

Keywords:

• Carbonic anhydrase
• sulfonamide
• inhibitor
• tumor
• acridine orange

Acknowledgements

This work was financed in part by a Distinguished Scientist Fellowship Program (DSFP) of King Saud University, Riyadh, Saudi Arabia.

Disclosure statement

One author (CTS) declares conflict of interest, being author of several patents in the field of CA inhibitors/activators. This research was financed by several EU projects (Euroxy, Metoxia, DeZnIt and Dynano). The other authors do not declare conflict of interest.

Additional information

Funding

This work was financed in part by a Distinguished Scientist Fellowship Program (DSFP) of King Saud University, Riyadh, Saudi Arabia.