Design, molecular docking, in vitro, and in vivo studies of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors with potential activity against hepatocellular carcinoma

Ibrahim H Eissa; Mohammed K Ibrahim; Ahmed M Metwaly; Amany Belal; Ahmed B M Mehany; Alsayed A Abdelhady; Mostafa A Elhendawy; Mohamed M Radwan; Mahmoud A ElSohly; Hazem A Mahdy

doi:10.1016/j.bioorg.2020.104532

Design, molecular docking, in vitro, and in vivo studies of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors with potential activity against hepatocellular carcinoma

Bioorg Chem. 2021 Feb:107:104532. doi: 10.1016/j.bioorg.2020.104532. Epub 2020 Dec 8.

Authors

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: Ibrahimeissa@azhar.edu.eg.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
³ Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
⁴ Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
⁵ Zoology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt.
⁶ Department of Anatomy, Faculty of Medicine, Helwan University, Cairo, Egypt.
⁷ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt.
⁸ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
⁹ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA.
¹⁰ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: hazem_hady2001@azhar.edu.eg.

PMID: 33334586
DOI: 10.1016/j.bioorg.2020.104532

Abstract

A series of new VEGFR-2 inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against hepatocellular carcinoma (HepG-2 cell line). Compound 29_b (IC₅₀ = 4.33 ± 0.2 µg/ml) was found to be the most potent derivative as it has showed to be more active than doxorubicin (IC₅₀ = 4.50 ± 0.2 µg/ml) and 78% of sorafenib activity (IC₅₀ = 3.40 ± 0.25 µg/ml). The inhibitory profiles against VEGFR-2 were also assessed for the most promising candidates (16_b, 20_c, 22_b, 24_a, 24_b, 28_c, 28_e, 29_a, 29_b and 29_c). Compounds 29_b, 29_c and 29_a exhibited potent inhibitory activities towards VEGFR-2 at IC₅₀ values of 3.1 ± 0.04, 3.4 ± 0.05 and 3.7 ± 0.06 µM, respectively, comparing sorafenib (IC₅₀ = 2.4 ± 0.05 µM). Furthermorer, compound 29_b induced apoptosis and arrested the cell cycle growth at G2/M phase. Additionally, in vivo antitumor experiments revealed that compounds 29_b and 29_c have significant tumor growth inhibition. The test of immuno-histochemical expression of activated caspase-3 revealed that there is a time-dependent increase in cleaved caspase-3 protein expression upon exposure of HepG-2 cells to compound 29_b. Moreover, the fibroblastic proliferative index test revealed that compound 29_b could attenuate liver fibrosis. Docking studies also supported the results concluded from the biological screening via prediction of the possible binding interactions of the target compounds with VEGFR-2 active sites using the crystal structure of VEGFR-2 downloaded from the Protein Data Bank, (PDB ID: 2OH4) using Discovery Studio 2.5 software. Further structural optimization of the most active candidates may serve as a useful strategy for getting new lead compounds in search for powerful and selective antineoplastic agents.

Keywords: Anticancer; Apoptosis; In vivo studies; Liver cancer; Molecular docking; Quinazolin-4(3H)-one; VEGFR-2 inhibitors.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / pathology
Cell Proliferation / drug effects
G1 Phase Cell Cycle Checkpoints / drug effects
G2 Phase Cell Cycle Checkpoints / drug effects
Hep G2 Cells
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / pathology
Male
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Quinazolinones / chemical synthesis
Quinazolinones / metabolism
Quinazolinones / pharmacokinetics
Quinazolinones / therapeutic use*
Rats
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolinones
Kdr protein, rat
Vascular Endothelial Growth Factor Receptor-2