Presently, dual targeting by a singlesmall moleculestands outas an effective cancer-fighting weapon. Carbonic anhydrase (CA) andvascular-endothelial growth factor (VEGF) are hypoxia-activatablegenes that are implicated in tumorigenesis and progression of hypoxictumors at different levels. Herein, we designed and synthesized 301,5-diaryl-1,2,4-triazole-tethered sulfonamides (11a-f, 12a-l, 13a-f, 15a-f) asnovel SLC-0111 analogues with dual CA IX/XII and VEGFR-2 inhibitoryactivities. The 4-fluorophenyl SLC-0111 tail was replaced by substituted1,5-diaryl-1,2,4-triazoles. Changing the sulfamoyl motif positionprovided regioisomers 11a-f and 12a-l. Elongation of the ureido linkeryielded derivatives 15a-f. Inhibitoryevaluations included a panel of hCAs (hCA I, II, IX, and XII) and screening against 60 cancer cell lines.Promising candidates were assessed for VEGFR-2 inhibition and selectivityand further evaluated on breast cancer cell lines (MCF-7 and T-47D)and the non-tumorigenic (MCF-10A) cells. Molecular docking studiesexplored the binding modes of the sulfonamides against hCA IX/XII and VEGFR-2 kinase.

1,5-Diaryl-1,2,4-triazole Ureas as New SLC-0111 Analogues Endowed with Dual Carbonic Anhydrase and VEGFR-2 Inhibitory Activities / Elsawi, Ahmed E.; Elbadawi, Mostafa M.; Nocentini, Alessio; Almahli, Hadia; Giovannuzzi, Simone; Shaldam, Moataz; Salem, Rofaida; Ibrahim, Tamer M.; Abdel-Aziz, Hatem A.; Supuran, Claudiu T.; Eldehna, Wagdy M.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 66:(2023), pp. 10558-10578. [10.1021/acs.jmedchem.3c00721]

1,5-Diaryl-1,2,4-triazole Ureas as New SLC-0111 Analogues Endowed with Dual Carbonic Anhydrase and VEGFR-2 Inhibitory Activities

Nocentini, Alessio;Giovannuzzi, Simone;Supuran, Claudiu T.;
2023

Abstract

Presently, dual targeting by a singlesmall moleculestands outas an effective cancer-fighting weapon. Carbonic anhydrase (CA) andvascular-endothelial growth factor (VEGF) are hypoxia-activatablegenes that are implicated in tumorigenesis and progression of hypoxictumors at different levels. Herein, we designed and synthesized 301,5-diaryl-1,2,4-triazole-tethered sulfonamides (11a-f, 12a-l, 13a-f, 15a-f) asnovel SLC-0111 analogues with dual CA IX/XII and VEGFR-2 inhibitoryactivities. The 4-fluorophenyl SLC-0111 tail was replaced by substituted1,5-diaryl-1,2,4-triazoles. Changing the sulfamoyl motif positionprovided regioisomers 11a-f and 12a-l. Elongation of the ureido linkeryielded derivatives 15a-f. Inhibitoryevaluations included a panel of hCAs (hCA I, II, IX, and XII) and screening against 60 cancer cell lines.Promising candidates were assessed for VEGFR-2 inhibition and selectivityand further evaluated on breast cancer cell lines (MCF-7 and T-47D)and the non-tumorigenic (MCF-10A) cells. Molecular docking studiesexplored the binding modes of the sulfonamides against hCA IX/XII and VEGFR-2 kinase.
2023
66
10558
10578
Goal 3: Good health and well-being
Elsawi, Ahmed E.; Elbadawi, Mostafa M.; Nocentini, Alessio; Almahli, Hadia; Giovannuzzi, Simone; Shaldam, Moataz; Salem, Rofaida; Ibrahim, Tamer M.; Abdel-Aziz, Hatem A.; Supuran, Claudiu T.; Eldehna, Wagdy M.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

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

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1356087
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 6
social impact