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Updated: May 12, 2025
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Design, Synthesis, and Photochemical Properties of Clickable Caged Compounds
Published on: October 15, 2019
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4-Substituted Pyridine-3-Sulfonamides as Carbonic Anhydrase Inhibitors Modified by Click Tailing: Synthesis,
Krzysztof Szafrański1, Jarosław Sławiński1, Anna Kawiak2
1Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
International Journal of Molecular Sciences
|May 7, 2025
Summary
Researchers developed novel pyridine-3-sulfonamides targeting cancer-related human carbonic anhydrases (hCA IX and hCA XII). Some compounds showed significant selectivity, offering potential for new cancer therapies.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Chemical Biology
Background:
- Human carbonic anhydrases (hCAs) are crucial enzymes involved in various physiological processes.
- Aberrant hCA activity, particularly isoforms IX and XII, is linked to cancer development and progression.
- Selective inhibition of cancer-associated hCAs is a promising therapeutic strategy.
Purpose of the Study:
- To synthesize and evaluate novel 4-substituted pyridine-3-sulfonamides as potential inhibitors of human carbonic anhydrases.
- To investigate the selectivity of these compounds against cancer-associated isoforms (hCA IX, hCA XII) versus other isoforms (hCA I, hCA II).
- To explore the structure-activity relationships and binding modes through molecular docking and cytostatic assays.
Main Methods:
- Synthesis of 4-substituted pyridine-3-sulfonamides via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry.
- In vitro enzymatic assays to determine inhibitory activity (KI values) against purified hCA I, II, IX, and XII.
- Molecular docking simulations to predict binding interactions within the hCA active sites.
- Cytostatic activity assays on selected cancer cell lines.
Main Results:
- A series of pyridine-3-sulfonamide derivatives were successfully synthesized and characterized.
- Compounds displayed varying inhibitory potencies, with KI values as low as 91 nM for hCA XII.
- Compound 4 showed 5.9-fold selectivity for hCA IX over hCA II, and compound 6 exhibited 23.3-fold selectivity between hCA IX and hCA XII.
- Molecular docking suggested selective interactions influenced by the substituent position relative to the sulfonamide group.
Conclusions:
- The synthesized pyridine-3-sulfonamides are potent inhibitors of human carbonic anhydrases.
- Specific compounds demonstrate promising selectivity profiles for cancer-associated isoforms, particularly hCA IX and hCA XII.
- These findings support the potential of targeting hCA IX and hCA XII with pyridine-3-sulfonamide-based inhibitors for cancer therapy.
