Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• Carbonic anhydrase (CA) enzyme inhibition is a key strategy for anti-cancer drug development.
• CA isoforms IX and XII are overexpressed in solid tumors, driving cancer progression.
• Targeting these specific CA isoforms offers a therapeutic avenue for cancer treatment.

Purpose of the Study:

• To design, synthesize, and characterize novel sulfonamides based on a coumarin scaffold.
• To evaluate the inhibitory activity and selectivity of these compounds against cancer-associated CA isoforms IX and XII.
• To identify potent and selective CA inhibitors for further preclinical development.

Main Methods:

• Synthesis of a novel series of coumarin-based sulfonamides.
• In vitro enzymatic assays to determine inhibitory activity (Ki values) against CA isoforms I, II, IX, and XII.
• Comparative analysis of compound potency against acetazolamide (AAZ) as a control.

Main Results:

• Several novel sulfonamides demonstrated potent and selective inhibition of CA IX and XII.
• Twelve compounds exhibited higher potency than AAZ against CA IX.
• Compound 18f showed significant inhibitory activity against CA IX and XII (Ki values of 21 nM and 5 nM, respectively).

Conclusions:

• The developed coumarin-based sulfonamides are effective inhibitors of tumor-associated carbonic anhydrase IX and XII.
• Compound 18f represents a promising novel inhibitor of CA IX and XII for potential anti-cancer applications.
• This study validates the coumarin scaffold for developing targeted CA inhibitors in oncology.