Cyclic secondary sulfonamides: unusually good inhibitors of cancer-related carbonic anhydrase enzymes

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Carbonic anhydrase IX (CA IX) is a key target for cancer therapies, particularly in hypoxic tumors.
• Developing selective CA IX inhibitors is crucial for effective treatment and minimizing side effects.
• While primary sulfonamides inhibit CAs broadly, secondary sulfonamides are typically weak inhibitors, with saccharin being a notable exception.

Purpose of the Study:

• To investigate the potential of modifying saccharin, a cyclic secondary sulfonamide, to enhance its affinity and selectivity for CA IX.
• To explore the structure-activity relationship of saccharin derivatives as CA IX inhibitors.
• To identify potent and selective CA IX inhibitors for cancer therapy.

Main Methods:

• Synthesized novel saccharin derivatives by conjugating hydrophobic or hydrophilic substituents.
• Assessed the inhibitory activity of these derivatives against CA IX using enzyme inhibition assays.
• Determined the selectivity profile by testing against major off-target carbonic anhydrase isozymes.

Main Results:

• A hydrophilic glycoconjugate derivative (compound 12) demonstrated significantly improved inhibition of CA IX (Ki = 49.5 nM) compared to saccharin (Ki = 103 nM).
• Compound 12 exhibited exceptional selectivity, with >1000-fold reduced inhibition of off-target CAs (Ki > 50000 nM).
• This level of selectivity surpasses that of traditional primary sulfonamide CA inhibitors.

Conclusions:

• Cyclic secondary sulfonamides, like saccharin derivatives, represent a promising scaffold for developing highly selective CA IX inhibitors.
• The developed glycoconjugate derivative shows potential as a potent therapeutic agent for hypoxic cancers.
• Further exploration of this class of compounds could lead to novel cancer-selective drugs.