Design, synthesis and evaluation of anticancer activity of new pyrazoline derivatives by down-regulation of VEGF: Molecular docking and apoptosis inducing activity

Rasha A Hassan; Soha H Emam; Dukhyun Hwang; Gun-Do Kim; Soha O Hassanin; Mona G Khalil; Amr M Abdou; Amr Sonousi

doi:10.1016/j.bioorg.2021.105487

Design, synthesis and evaluation of anticancer activity of new pyrazoline derivatives by down-regulation of VEGF: Molecular docking and apoptosis inducing activity

Bioorg Chem. 2022 Jan:118:105487. doi: 10.1016/j.bioorg.2021.105487. Epub 2021 Nov 13.

Authors

Rasha A Hassan¹, Soha H Emam¹, Dukhyun Hwang², Gun-Do Kim², Soha O Hassanin³, Mona G Khalil⁴, Amr M Abdou⁵, Amr Sonousi⁶

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
² Department of Microbiology, College of Natural Sciences, Pukyong National University, Busan 48513, Korea.
³ Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
⁴ Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
⁵ Department of Microbiology and Immunology, National Research Centre, Dokki, Giza, 12622, Egypt.
⁶ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; University of Hertfordshire hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt. Electronic address: [email protected].

PMID: 34798455
DOI: 10.1016/j.bioorg.2021.105487

Abstract

Two series of pyrazoline compounds were designed and synthesized as antiproliferative agents by VEGFR pathway inhibition. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines. Compound 3f exhibited the highest anticancer activity on the ovarian cell line (OVCAR-4) with IC₅₀ = 0.29 μM and on the breast cell line (MDA-MB-468) with IC₅₀ = 0.35 μM. It also exhibited the highest selectivity index (SI = 74). Compound 3f caused cell cycle arrest in OVCAR-4 cell line at the S phase which consequently inhibited cell proliferation and induced apoptosis. Moreover, 3f showed potent down-regulation of VEGF and p-VEGFR-2. Docking studies showed that compound 3f interacts in a similar pattern to axitinib on the VEGFR-2 receptor. The same compound was also able to fit into the gorge of STAT3 binding site, the transcription factor for VEGF, which explains the VEGF down-regulation.

Keywords: Anticancer; Apoptosis; Cell cycle analysis; Pyrazoline; STAT3; VEGF.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Down-Regulation / drug effects
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor A / antagonists & inhibitors*
Vascular Endothelial Growth Factor A / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
VEGFA protein, human
Vascular Endothelial Growth Factor A