Inhibitory, Anticancer Efficacy and Structural Insights of a Novel Ethyl 1-Hydroxy-3-Oxo-1-Phenylisoindoline-2-Sulfonate Compound Selectively Targeting Human CA IX and CA XII Carbonic Anhydrase, Ferroptosis-Mediated Cell Death.
- 1Department of Molecular Biology and Genetics, Atatürk University, Erzurum, Turkey.
- 2Department of Chemistry, Faculty of Sciences, Atatürk University, Erzurum, Turkey.
- 3Department of Pathology, Faculty of Veterinary Medicine, Cumhuriyet University, Sivas, Turkey.
Abstract
Carbonic anhydrase (CA) isoforms IX and XII are critical in anticancer drug development due to their essential roles in regulating pH and hypoxic conditions. In this study, the inhibitory potential of ethyl-1-hydroxy-3-oxo-1-phenylisoindoline-2-sulfonate (1), synthesized via click chemistry, was evaluated against hCA IX and hCA XII. The cellular effects of compound on human breast cancer (MCF-7 cells) were investigated using a combination of viability, oxidative stress, and molecular level. Compound exhibited stronger inhibitory activity than the acetazolamide (AAZ), with Ki values of 11.48 ± 4.18 nM for hCA IX and 9.32 ± 2.35 nM for hCA XII. The compound exhibited a higher binding affinity to hCA IX with -8.8 kcal/mol docking score. While no cytotoxic effect was observed on MCF-10A cells, a significant dose-dependent reduction was observed in cell viability, confirmed loss of membrane integrity in cancer cells. ROS levels were decreased at higher concentrations, indicating that the toxicity was independent of ROS production. Caspase-3 and LC3B expression showed strong positivity at moderate concentrations, suggesting activation of apoptotic and autophagic pathways. GPX4 and TFRC fluorescence intensities were markedly decreased that disruption of redox homeostasis and iron metabolism. These findings indicate that compound is a promising lead molecule for the development of next-generation anticancer agents targeting tumor-associated CA isoforms.
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BibTeX
@article{keteci2026inhibitory,
title = {{Inhibitory, Anticancer Efficacy and Structural Insights of a Novel Ethyl 1-Hydroxy-3-Oxo-1-Phenylisoindoline-2-Sulfonate Compound Selectively Targeting Human CA IX and CA XII Carbonic Anhydrase, Ferroptosis-Mediated Cell Death.}},
author = {Funda Keteci and Songul Bayrak and Ufuk Atmaca and Mustafa Özkaraca and Azada Aliyeva and Buket Bakan},
journal = {Cell biochemistry and function},
year = {2026},
month = nov,
doi = {10.1002/cbf.70336},
url = {https://europepmc.org/article/MED/42968633},
note = {CC BY},
}
RIS
TY - JOUR
TI - Inhibitory, Anticancer Efficacy and Structural Insights of a Novel Ethyl 1-Hydroxy-3-Oxo-1-Phenylisoindoline-2-Sulfonate Compound Selectively Targeting Human CA IX and CA XII Carbonic Anhydrase, Ferroptosis-Mediated Cell Death.
AU - Funda Keteci
AU - Songul Bayrak
AU - Ufuk Atmaca
AU - Mustafa Özkaraca
AU - Azada Aliyeva
AU - Buket Bakan
PY - 2026
DA - 2026/11/01
JO - Cell biochemistry and function
DO - 10.1002/cbf.70336
UR - https://europepmc.org/article/MED/42968633
AB - Carbonic anhydrase (CA) isoforms IX and XII are critical in anticancer drug development due to their essential roles in regulating pH and hypoxic conditions. In this study, the inhibitory potential of ethyl-1-hydroxy-3-oxo-1-phenylisoindoline-2-sulfonate (1), synthesized via click chemistry, was evaluated against hCA IX and hCA XII. The cellular effects of compound on human breast cancer (MCF-7 cells) were investigated using a combination of viability, oxidative stress, and molecular level. Compound exhibited stronger inhibitory activity than the acetazolamide (AAZ), with Ki values of 11.48 ± 4.18 nM for hCA IX and 9.32 ± 2.35 nM for hCA XII. The compound exhibited a higher binding affinity to hCA IX with -8.8 kcal/mol docking score. While no cytotoxic effect was observed on MCF-10A cells, a significant dose-dependent reduction was observed in cell viability, confirmed loss of membrane integrity in cancer cells. ROS levels were decreased at higher concentrations, indicating that the toxicity was independent of ROS production. Caspase-3 and LC3B expression showed strong positivity at moderate concentrations, suggesting activation of apoptotic and autophagic pathways. GPX4 and TFRC fluorescence intensities were markedly decreased that disruption of redox homeostasis and iron metabolism. These findings indicate that compound is a promising lead molecule for the development of next-generation anticancer agents targeting tumor-associated CA isoforms.
SN - 0263-6484
SN - 1099-0844
ER -