Among the chemotypes studied for selective inhibition of tumour-associated carbonic anhydrases (CAs), SLC-0111, a ureido-bearing benzenesulfonamide CA IX inhibitor, displayed promising antiproliferative effects in cancer cells in vitro and in vivo, being in Phase Ib/II clinical development. To explore the structural characteristics required for better discrimination of less conserved regions of the enzyme, we investigate the incorporation of the urea linker into an imidazolidin-2-one cycle, a modification already explored previously for obtaining CA inhibitors. This new library of compounds inhibited potently four different hCAs in the nanomolar range with a different isoform selectivity profile compared to the lead SLC-0111. Several representative CA IX inhibitors were tested for their efficacy to inhibit the proliferation of glioblastoma, pancreatic, and breast cancer cells expressing CA IX, in hypoxic conditions. Unlike previous literature data on SLC-149, a structurally related sulphonamide to compounds investigated here, our data reveal that these derivatives possess promising anti-proliferative effects, comparable to those of SLC-0111.

Benzenesulfonamides with different rigidity-conferring linkers as carbonic anhydrase inhibitors: an insight into the antiproliferative effect on glioblastoma, pancreatic, and breast cancer cells

Ronca R.
;
Rezzola S.;Filiberti S.;Turati M.;
2022-01-01

Abstract

Among the chemotypes studied for selective inhibition of tumour-associated carbonic anhydrases (CAs), SLC-0111, a ureido-bearing benzenesulfonamide CA IX inhibitor, displayed promising antiproliferative effects in cancer cells in vitro and in vivo, being in Phase Ib/II clinical development. To explore the structural characteristics required for better discrimination of less conserved regions of the enzyme, we investigate the incorporation of the urea linker into an imidazolidin-2-one cycle, a modification already explored previously for obtaining CA inhibitors. This new library of compounds inhibited potently four different hCAs in the nanomolar range with a different isoform selectivity profile compared to the lead SLC-0111. Several representative CA IX inhibitors were tested for their efficacy to inhibit the proliferation of glioblastoma, pancreatic, and breast cancer cells expressing CA IX, in hypoxic conditions. Unlike previous literature data on SLC-149, a structurally related sulphonamide to compounds investigated here, our data reveal that these derivatives possess promising anti-proliferative effects, comparable to those of SLC-0111.
File in questo prodotto:
File Dimensione Formato  
2022 JEnzyme InhinbMedChem_Corradori.pdf

accesso aperto

Tipologia: Full Text
Licenza: Dominio pubblico
Dimensione 2.4 MB
Formato Adobe PDF
2.4 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/564906
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 18
social impact