Di-meta-Substituted Fluorinated Benzenesulfonamides as Potent and Selective Anticancer Inhibitors of Carbonic...

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Structural Biology

Background:

• Targeting cancer-specific carbonic anhydrase isozymes IX (CAIX) and XII (CAXII) is crucial for cancer therapy.
• High homology in binding sites among carbonic anhydrase (CA) isozymes presents a significant challenge for developing selective inhibitors.

Purpose of the Study:

• To design and synthesize novel di-meta-substituted fluorinated benzenesulfonamides.
• To achieve high affinity and selectivity for CAIX over other CA isozymes.
• To elucidate the structural basis of ligand-protein interactions for CAIX and CAXII.

Main Methods:

• Chemical synthesis of di-meta-substituted fluorinated benzenesulfonamides.
• In vitro assays to determine binding affinity and selectivity against various CA isozymes.
• X-ray crystallography to determine the co-crystal structures of CAIX and CAXII with synthesized compounds.

Main Results:

• Synthesized compounds demonstrated up to 10-fold improvement in affinity for CAIX, achieving low picomolar binding.
• Achieved up to 1000-fold selectivity for CAIX over off-target CA isozymes.
• Crystal structures revealed detailed protein-ligand interactions and compound conformations.

Conclusions:

• The developed compounds represent potent and selective inhibitors of CAIX.
• The structural insights provide a foundation for further optimization of anticancer drug candidates.
• These findings support the potential of these compounds as therapeutic agents for cancer treatment with minimized side effects.