2. Academic Validation
  3. Discovery of indolinone-bearing benzenesulfonamides as new dual carbonic anhydrase and VEGFR-2 inhibitors possessing anticancer and pro-apoptotic properties

Discovery of indolinone-bearing benzenesulfonamides as new dual carbonic anhydrase and VEGFR-2 inhibitors possessing anticancer and pro-apoptotic properties

  • Eur J Med Chem. 2023 Nov 5;259:115707. doi: 10.1016/j.ejmech.2023.115707.
Samaa Saied 1,  Moataz Shaldam 1,  Mostafa M Elbadawi 1,  Simone Giovannuzzi 2,  Alessio Nocentini 2,  Hadia Almahli 3,  Rofaida Salem 1,  Tamer M Ibrahim 1,  Claudiu T Supuran 4,  Wagdy M Eldehna 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 2 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 3 Department of Chemistry, University of Cambridge, CB2 1EW, Cambridge, United Kingdom.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com.
PMID: 37556946 DOI: 10.1016/j.ejmech.2023.115707
Abstract

In the current medical era, the utilization of a single small molecule to simultaneously target two distinct molecular targets is emerging as a highly effective strategy in the battle against Cancer. Carbonic Anhydrase (CA) and Vascular-Endothelial Growth Factor (VEGF) are genes that are activated in response to low oxygen levels (hypoxia) and play a role in the development and progression of tumors in hypoxic conditions. Herein we report the design, synthesis, and biological assessment of a series of novel indolinone-based benzenesulfonamides (8a-k, 11a-d, 15a-d, and 16) as potential dual inhibitors for cancer-associated hCA IX/XII and VEGFR-2. All the synthesized sulfonamides were assessed for their inhibitory effect against four CA isoforms I, II, IX, and XII where they displayed varying degrees of hCA inhibition. The most effective and selective hCA IX and XII inhibitors 8g, 8j and 15b were chosen to be tested for their in vitro inhibitory impact against VEGFR-2 as well as their antiproliferative impact against VEGFR-2 overexpressing MDA-MB-231 and MCF-7 breast Cancer cells. Furthermore, molecular docking studies were conducted within the hCA IX, XII, and VEGFR-2 active sites to explain the observed inhibitory results.

Keywords

Angiogenesis; Anticancer agents; Hypoxic tumors; Molecular modeling; Tail approach; VEGFR-2 inhibitors.

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