2. Academic Validation
  3. 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

  • Eur J Med Chem. 2021 Oct 15:222:113589. doi: 10.1016/j.ejmech.2021.113589.
Dmitry Dar'in 1,  Grigory Kantin 1,  Stanislav Kalinin 1,  Tatiana Sharonova 1,  Alexander Bunev 2,  Gennady I Ostapenko 2,  Alessio Nocentini 3,  Vladimir Sharoyko 1,  Claudiu T Supuran 4,  Mikhail Krasavin 5
Affiliations

Affiliations

  • 1 Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation.
  • 2 Medicinal Chemistry Center, Togliatti State University, Togliatti, 445020, Russian Federation.
  • 3 Neurofarba Department, Universita Degli Studi di Firenze, Florence, 50019, Italy.
  • 4 Neurofarba Department, Universita Degli Studi di Firenze, Florence, 50019, Italy. Electronic address: claudiu.supuran@unifi.it.
  • 5 Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation. Electronic address: m.krasavin@spbu.ru.
PMID: 34147910 DOI: 10.1016/j.ejmech.2021.113589
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 KI 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 IC50 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.

Keywords

Antiproliferative agents; Apoptosis induction; Cancer cells; Carbonic anhydrase; Caspase activation; Coumarins; Enzyme inhibitors; Hypoxic environment; MTT-Test; Nanomolar inhibition; Primary sulfonamides; Stopped-flow assay.

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