2. Academic Validation
  3. Fragment-based design and synthesis of coumarin-based thiazoles as dual c-MET/STAT-3 inhibitors for potential antitumor agents

Fragment-based design and synthesis of coumarin-based thiazoles as dual c-MET/STAT-3 inhibitors for potential antitumor agents

  • Bioorg Chem. 2024 Oct:151:107682. doi: 10.1016/j.bioorg.2024.107682.
Bassem H Naguib 1,  Heba A Elsebaie 2,  Mohamed S Nafie 3,  Samy Mohamady 4,  Nader R Albujuq 5,  Aya Samir Ayed 6,  Dina Nada 7,  Ahmed F Khalil 2,  Salma M Hefny 2,  Haytham O Tawfik 8,  Moataz A Shaldam 9
Affiliations

Affiliations

  • 1 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 3 Department of Chemistry, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt.
  • 5 Department of Chemistry, School of Science, The University of Jordan, Amman 11942, Jordan.
  • 6 Zoology Department, Faculty of Science, Suez Canal University, P.O. 41522, Ismailia, Egypt.
  • 7 Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University, Egypt.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box 33516, Kafrelsheikh, Egypt.
PMID: 39137597 DOI: 10.1016/j.bioorg.2024.107682
Abstract

c-MET and STAT-3 are significant targets for Cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of Cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS Cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 μM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced Apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall Apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.

Keywords

CNS cancer; Coumarin-based thiazoles; Dual c-MET & STAT-3 inhibitors; Molecular docking.

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