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Investigation of 3-sulfamoyl coumarins against cancer-related IX and XII isoforms of human carbonic anhydrase as well as cancer cells leads to the discovery of 2-oxo-2H-benzo[h]chromene-3-sulfonamide - A new caspase-activating proapoptotic agent.
Investigation of 3-sulfamoyl coumarins against cancer-related IX and XII isoforms of human carbonic anhydrase as well as cancer cells leads to the discovery of 2-oxo-2H-benzo[h]chromene-3-sulfonamide - A new caspase-activating proapoptotic agent.
- Source :
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European journal of medicinal chemistry [Eur J Med Chem] 2021 Oct 15; Vol. 222, pp. 113589. Date of Electronic Publication: 2021 Jun 10. - Publication Year :
- 2021
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Abstract
- Herein we report the synthesis of a set of seventeen 3-sulfonamide substituted coumarin derivatives. Prepared compounds were tested in vitro for inhibition of four physiologically relevant isoforms of the metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1). Several coumarin sulfonamides displayed low nanomolar K <subscript>I</subscript> values against therapeutically relevant hCA II, IX, and XII, whereas they did not potently inhibit hCA I. Some of these compounds exerted a concentration-dependent antiproliferative action toward RT4 human bladder cancer and especially A431 human epidermoid carcinoma cell lines. In the meantime, the viability of non-tumorigenic hTERT immortalized human foreskin fibroblast cell line Bj-5ta was not significantly affected by the obtained derivatives. Interestingly, compound 10q (2-oxo-2H-benzo [h]chromene-3-sulfonamide) showed a profound and selective dose-dependent inhibition of A431 cell growth with low nanomolar IC <subscript>50</subscript> values. We demonstrated that 10q possessed a concentration-dependent apoptosis induction activity associated with caspase 3/7 activation in cancer cells. As carbonic anhydrase isoforms in question were not potently inhibited by this compound, its antiproliferative effects likely involve other mechanisms, such as DNA intercalation. Compound 10q clearly represents a viable lead for further development of new-generation anticancer agents.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antigens, Neoplasm metabolism
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Carbonic Anhydrase IX metabolism
Carbonic Anhydrase Inhibitors chemical synthesis
Carbonic Anhydrase Inhibitors chemistry
Cell Proliferation drug effects
Cells, Cultured
Coumarins chemical synthesis
Coumarins chemistry
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Carbonic Anhydrase IX antagonists & inhibitors
Carbonic Anhydrase Inhibitors pharmacology
Carbonic Anhydrases metabolism
Coumarins pharmacology
Drug Discovery
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 222
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34147910
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113589