2. Academic Validation
  3. Design, synthesis, and anticancer evaluation of N-sulfonylpiperidines as potential VEGFR-2 inhibitors, apoptotic inducers

Design, synthesis, and anticancer evaluation of N-sulfonylpiperidines as potential VEGFR-2 inhibitors, apoptotic inducers

  • Bioorg Chem. 2024 Feb 7:145:107157. doi: 10.1016/j.bioorg.2024.107157.
Walid E Elgammal 1,  Ahmed H Halawa 2,  Ibrahim H Eissa 3,  Hazem Elkady 3,  Ahmed M Metwaly 4,  Saber M Hassan 2,  Ahmed M El-Agrody 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt. Electronic address: walidebaied.sci85@azhar.edu.eg.
  • 2 Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt.
  • 3 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
  • 4 Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt; Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
PMID: 38340473 DOI: 10.1016/j.bioorg.2024.107157
Abstract

A new panel of N-sulfonylpiperidine derivatives has been designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Anti-proliferative activities of the synthesized members were tested against colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast Cancer (MCF-7) cell lines. Compounds 3a, 4, 8, and 9 showed the highest activities against the tested cell lines. In particular, compound 8 showed excellent activities against HCT-116, HepG-2, and MCF-7 with IC50 values of 3.94, 3.76, and 4.43 μM, respectively. Such IC50 values are comparable to vinblastine (IC50 = 3.21, 7.35, 5.83 μM, respectively) and doxorubicin (IC50 = 6.74, 7.52, 8.19 μM, respectively). In vitro VEGFR-2 inhibitory activity of the most promising molecules (3a, 4, 8, and 9) indicated that compound 8 is the highest VEGFR-2 inhibitor with an IC50 of 0.0554 μM, compared to sorafenib (IC50 = 0.0416 μM). The most promising candidates (3a, 4, 8, and 9) were subjected to flow cytometry analyses to assess their effects on the cell cycle behavior and the apoptotic power against the three tested cell lines (HCT-116, HepG-2, and MCF-7). The tested compound arrested the tumor cells at both the G2/M and Pre-G1 phases. In addition, compound 9 was proved as the most effective apoptotic inducer among the tested compounds against the tested cells. Molecular docking studies against VEGFR-2 (PDB ID: 2OH4) revealed good binding modes of the synthesized compound similar to that of sorafenib. Computational investigation of ADMET parameters revealed the drug-likeness of the synthesized compounds.

Keywords

Anticancer; Apoptosis; Molecular docking; N-Sulfonylpiperidine; VEGFR-2 inhibitors.

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