Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors

Mohamed A Zeidan; Amany S Mostafa; Rania M Gomaa; Laila A Abou-Zeid; Mohamed El-Mesery; Magda A-A El-Sayed; Khalid B Selim

doi:10.1016/j.ejmech.2019.02.050

Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors

Eur J Med Chem. 2019 Apr 15:168:315-329. doi: 10.1016/j.ejmech.2019.02.050. Epub 2019 Feb 22.

Authors

Mohamed A Zeidan¹, Amany S Mostafa², Rania M Gomaa², Laila A Abou-Zeid³, Mohamed El-Mesery⁴, Magda A-A El-Sayed¹, Khalid B Selim⁵

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Dammeitta, Egypt.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University, Gamsaa, Egypt.
⁴ Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
⁵ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: khbselim@mans.edu.eg.

PMID: 30826508
DOI: 10.1016/j.ejmech.2019.02.050

Abstract

Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC₅₀ values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC₅₀ = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.

Keywords: A549; Apoptosis; Binding DFG motif; Cell cycle analysis; Kinase inhibition; Picolinamide; VEGFR-2.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Docking Simulation*
Molecular Structure
Picolinic Acids / chemical synthesis
Picolinic Acids / chemistry
Picolinic Acids / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Picolinic Acids
Protein Kinase Inhibitors
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2
picolinamide