2. Academic Validation
  3. Synthesis, biological evaluation, and in silico studies of potential activators of apoptosis and carbonic anhydrase inhibitors on isatin-5-sulfonamide scaffold

Synthesis, biological evaluation, and in silico studies of potential activators of apoptosis and carbonic anhydrase inhibitors on isatin-5-sulfonamide scaffold

  • Eur J Med Chem. 2022 Jan 15:228:113997. doi: 10.1016/j.ejmech.2021.113997.
Stepan K Krymov 1,  Alexander M Scherbakov 2,  Diana I Salnikova 2,  Danila V Sorokin 2,  Lyubov G Dezhenkova 1,  Ivan V Ivanov 1,  Daniela Vullo 3,  Viviana De Luca 4,  Clemente Capasso 4,  Claudiu T Supuran 5,  Andrey E Shchekotikhin 6
Affiliations

Affiliations

  • 1 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia.
  • 2 Blokhin National Medical Center of Oncology, 24 Kashirskoye Shosse, Moscow, 115522, Russia.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy.
  • 4 Institute of Biosciences and Bioresources, CNR, Via Pietro Castellino 111, 80131, Napoli, Italy.
  • 5 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
  • 6 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow, 119021, Russia. Electronic address: shchekotikhin@gause-inst.ru.
PMID: 34902732 DOI: 10.1016/j.ejmech.2021.113997
Abstract

Carbonic Anhydrase IX is a promising target for the search for new antitumor compounds with improved properties. Using the molecular hybridization approach, on the basis of structures of a selective Carbonic Anhydrase IX inhibitor 3 and an activator of Apoptosis 2 (1), a series of 1-substituted isatin-5-sulfonamides 5a-5u were designed and synthesized. The study of the inhibitory activity of isatin-5-sulfonamides showed the ability to inhibit I, II, IX, XII isoforms at nano- and micromolar concentrations. Docking of compounds 5e and 5k into the active site of II and IX Carbonic Anhydrase isoforms showed the coordination of sulfonamidate anions with zinc cations, as well as a number of additional hydrophobic interactions. The trifluoromethylthio derivative 5r suppressed the growth of tumor cells at low micromolar concentrations, maintaining activity on resistant lines and under hypoxic conditions. Immunoblotting of MCF7 cells treated with the 5r revealed its antiestrogenic activity and ability to activate Apoptosis in tumor cells.

Keywords

2,3-Dioxoindoline-5-sulfonamide; Antiproliferative activity; Apoptosis; Apoptosis activator; Carbonic anhydrases; Estrogen α-receptor; Hypoxia.

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