Glycosidic carbonic anhydrase IX inhibitors: a sweet approach against cancer

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Tumor-associated carbonic anhydrase (CA) isoforms IX and XII are key targets for cancer therapeutics, particularly in hypoxic tumors.
• Drug design for selective CA IX inhibitors has advanced, focusing on zinc-binding groups, scaffolds, and side chains.

Purpose of the Study:

• To review the latest developments in the design of specific carbonic anhydrase IX inhibitors.
• To highlight the role of the sugar approach in developing potent CA IX inhibitors for cancer therapy.

Main Methods:

• X-ray crystallography has been instrumental in understanding the structural basis for CA IX inhibitor design.
• Structure-activity relationship studies guide the development of inhibitors with improved potency and selectivity.

Main Results:

• The incorporation of sugar moieties into sulfonamide-based CA inhibitors has yielded highly potent CA IX inhibitors.
• These inhibitors demonstrate efficacy in impairing primary tumor growth and metastasis in preclinical cancer models.

Conclusions:

• The sugar approach is a significant research area for developing specific CA IX inhibitors.
• Sulfonamides, sulfamates, sulfamides, and coumarins incorporating sugar moieties show excellent in vitro and in vivo activity.