2. Academic Validation
  3. Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

  • J Med Chem. 2024 May 9;67(9):7406-7430. doi: 10.1021/acs.jmedchem.4c00239.
Salma M Hefny 1,  Tarek F El-Moselhy 1,  Nabaweya El-Din 1,  Simone Giovannuzzi 2,  Thamer Bin Traiki 3,  Mansoor-Ali Vaali-Mohammed 3,  Ahmed M El-Dessouki 4,  Koki Yamaguchi 5,  Masaharu Sugiura 5,  Moataz A Shaldam 6,  Claudiu T Supuran 2,  Maha-Hamadien Abdulla 3,  Wagdy M Eldehna 6,  Haytham O Tawfik 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, 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 Surgery, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
  • 4 Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, sixth of October City, Giza 12566, Egypt.
  • 5 Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
PMID: 38642371 DOI: 10.1021/acs.jmedchem.4c00239
Abstract

A dual-targeting approach is predicted to yield better Cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential Carbonic Anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate Cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and Bax, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

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