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

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.

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