2. Academic Validation
  3. Design and synthesis of new 1,2,3-triazole derivatives as VEGFR-2/telomerase downregulatory candidates endowed with apoptotic potential for cancer treatment

Design and synthesis of new 1,2,3-triazole derivatives as VEGFR-2/telomerase downregulatory candidates endowed with apoptotic potential for cancer treatment

  • Bioorg Chem. 2025 Mar:156:108159. doi: 10.1016/j.bioorg.2025.108159.
Ahmed A Al-Karmalawy 1,  Mohamed A Zeidan 2,  Ayman Abo Elmaaty 3,  Marwa Sharaky 4,  Asmaa S A Yassen 5,  Eman F Khaleel 6,  Wagdy M Eldehna 7,  Heba F Ashour 8
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 3 Medicinal Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt; Medicinal Chemistry Department, Clinical Pharmacy Program, East Port Said National University, Port Said 42526, Egypt.
  • 4 Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt.
  • 5 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt.
  • 6 Department of Medical Physiology, College of Medicine, King Khalid University, Asir 61421, Saudi Arabia.
  • 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 Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt.
PMID: 39823817 DOI: 10.1016/j.bioorg.2025.108159
Abstract

In this current work, we dedicated efforts to designing and synthesizing new 1,2,3-triazole-analogues (5a-d), (6a-d), and (7a-c) to act as dual VEGFR-2 and Telomerase inhibitors with promising apoptotic potential. The synthesized analogues were examined against eleven diverse types of Cancer cells and two normal cells to assess their ability to inhibit cell growth (GI%). Obviously, compound 7b showed the best average GI% (75.69 %) surpassing the average GI% of Dox (65.79 %). Compound 5d showed the lowest IC50 values (25.86 and 51.91 µM) against HNO-97 and FaDu Cancer cells, respectively. Besides, compound 5a exhibited the lowest IC50 value (15.46 µM) against HCT116, whereas compound 6b revealed the lowest IC50 value (31.14 µM) against HuH7. Besides, candidates 5a, 5b, 5d, and 7a showed prominent inhibitory results towards VEGFR-2 protein with decreasing its expression by 0.33, 0.42, 0.38 and 0.26-fold change, respectively. However, compounds 5a, 5b, 5d, and 7a showed promising inhibitory results towards Telomerase protein and decreased its expression by 0.60, 0.50, 0.52, and 0.44-fold change, respectively. Additionally, it was clear that compound 5a was able to upregulate the expression of Caspases 3, 8, and 9 proteins by 2.19, 1.83, and 1.62-fold change, respectively. Besides, 5a was able to downregulate the expression of CDK-2, CDK-4, and CDK-6 proteins by 0.50, 0.43, and 0.13-fold change, respectively. Obviously, compound 5a halted the cell cycle at the G1, S, and G2-M phases in HCT116 cells. Subsequently, the synthesized 1,2,3-triazole analogues can be treated as lead VEGFR-2 and Telomerase inhibitors with potential apoptotic activity for future optimization and Cancer treatment.

Keywords

1,2,3-Triazole; Apoptotic markers; Multi-target; Telomerase; VEGFR-2.

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