2. Academic Validation
  3. Novel inhibitors of oncogenic Wnt/TCF-4/β-catenin signaling pathway: Design, synthesis, molecular docking studies and apoptosis inducing activity of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4-thiadiazolopyrimido-indole hybrids

Novel inhibitors of oncogenic Wnt/TCF-4/β-catenin signaling pathway: Design, synthesis, molecular docking studies and apoptosis inducing activity of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4-thiadiazolopyrimido-indole hybrids

  • Bioorg Chem. 2025 Apr:157:108285. doi: 10.1016/j.bioorg.2025.108285.
Mai A E Mourad 1,  Ahmed A E Mourad 2,  Ayman Abo Elmaaty 3,  Amal Hofni 4,  Ahmed E Khodir 5,  Esam M Aboubakr 6,  Wagdy M Eldehna 7,  Ahmed A Al-Karmalawy 8
Affiliations

Affiliations

  • 1 Medicinal Chemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt; Medicinal Chemistry Department, Pharmacology and Toxicology Department, Faculty of Pharmacy, East Port-Said National University, Port-Said, Egypt. Electronic address: mai.mourad@pharm.psu.edu.eg.
  • 2 Pharmacology and Toxicology Department, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt; Medicinal Chemistry Department, Pharmacology and Toxicology Department, Faculty of Pharmacy, East Port-Said National University, Port-Said, Egypt. Electronic address: ahmed.mourad@pharm.psu.edu.eg.
  • 3 Medicinal Chemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt. Electronic address: ayman.mohamed@pharm.psu.edu.eg.
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt. Electronic address: amal.gaber@svu.edu.eg.
  • 5 Department of Pharmacology, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt. Electronic address: akhodir@horus.edu.eg.
  • 6 Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt. Electronic address: esam_pharma@svu.edu.eg.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria; Canal El Mahmoudia St., Alexandria 21648, Egypt.
  • 8 Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Mashreq, Baghdad 10023, Iraq; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt. Electronic address: akarmalawy@horus.edu.eg.
PMID: 40043386 DOI: 10.1016/j.bioorg.2025.108285
Abstract

Wnt pathway is vital for survival of cancer-initiating cells. β-catenin plays a crucial role in Wnt pathway through interaction with TCF-4 to transcribe oncogenes. β-catenin activation suppresses immune cell infiltration into Cancer cells and promotes resistance to chemotherapeutic drugs. In order to target Wnt/TCF-4/β-catenin pathway, a novel series of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4 thiadiazolopyrimido-indole hybrids were designed, synthesized and evaluated for their β-catenin/TCF-4 inhibitory and apoptotic inducing activities. Cytotoxicity of the synthesized hybrids was evaluated against HCT-116, A549 and HepG2 cell lines. Of the synthesized hybrids, 6a, 8b and 12b hybrids elicited superior cytotoxic activity compared to quercetin against the tested cell lines. These hybrids were able to significantly suppress β-catenin and its down-stream signaling target TCF-4 in a dose-dependent manner in HCT-116 cell line. They up-regulated p53, Caspase-3, Caspase-8, caspase-9 levels and Bax protein expression as well as down-regulated Bcl-2 protein expression. They successfully arrested cell cycle in pre-G1 phase and G0/G1 phase. The synthesized hybrids achieved efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

Keywords

Apoptosis; Indole; Pyrimidine; TCF-4/β-catenin; Wnt pathway.

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