Design, synthesis, and cytotoxicity screening of new synthesized imidazolidine-2-thiones as VEGFR-2 enzyme inhibitors

Islam Zaki; Heba M M Ramadan; El-Sherbiny H El-Sayed; Mohamed Abd El-Moneim

doi:10.1002/ardp.202000121

Design, synthesis, and cytotoxicity screening of new synthesized imidazolidine-2-thiones as VEGFR-2 enzyme inhibitors

Arch Pharm (Weinheim). 2020 Nov;353(11):e2000121. doi: 10.1002/ardp.202000121. Epub 2020 Aug 5.

Authors

Islam Zaki¹, Heba M M Ramadan², El-Sherbiny H El-Sayed², Mohamed Abd El-Moneim²

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
² Chemistry Department, Faculty of Science, Port Said University, Port Said, Egypt.

PMID: 32757353
DOI: 10.1002/ardp.202000121

Abstract

A series of imidazolin-2-thione derivatives was synthesized and structurally confirmed through the use of different spectroscopic techniques such as infrared, nuclear magnetic resonance, and mass spectrometry along with elemental analyses. The breast cancer cell line MCF-7 was utilized in the evaluation of the cytotoxic activity of the prepared molecules. The tested molecules 3 and 7 exhibited the best results on MCF-7 cells, with mean IC₅₀ values of 3.26 and 4.31 µM, respectively. The results of the VEGFR-2 assay indicated that compounds 3 and 7 displayed a good inhibition of the VEGFR-2 kinase enzyme. Additionally, DNA flow cytometry of compounds 3 and 7 showed cell cycle arrest at the G0/G1 phase, cell apoptosis, and marked DNA fragmentation in MCF-7 cells. Finally, compounds 3 and 7 were proved to upregulate the activation of effector caspase-3/7, as presented by the caspase-3/7 green flow cytometry assay.

Keywords: VEGFR-2; annexin-V; caspase-3/7; cell cycle analysis; imidazolidine.

Publication types

Comparative Study

MeSH terms

Angiogenesis Inhibitors / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / pathology
Caspase 3 / metabolism
Caspase 7 / metabolism
Cell Cycle Checkpoints / drug effects
Drug Design
Ethylenethiourea / analogs & derivatives
Ethylenethiourea / pharmacology*
Female
Humans
MCF-7 Cells
Molecular Docking Simulation
Molecular Structure
Molecular Targeted Therapy
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Angiogenesis Inhibitors
Protein Kinase Inhibitors
Ethylenethiourea
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2
CASP3 protein, human
CASP7 protein, human
Caspase 3
Caspase 7