Abstract
In this work, the natural piperine moiety was utilised to develop two sets of piperine-based amides (5a-i) and ureas (8a-y) as potential anticancer agents. The anticancer action was assessed against triple negative breast cancer (TNBC) MDA-MB-231, ovarian A2780CP and hepatocellular HepG2 cancer cell lines. In particular, 8q stood out as the most potent anti-proliferative analogue against TNBC MDA-MB-231 cells with IC50 equals 18.7 µM, which is better than that of piperine (IC50 = 47.8 µM) and 5-FU (IC50 = 38.5 µM). Furthermore, 8q was investigated for its possible mechanism of action in MDA-MB-231 cells via Annexin V-FITC apoptosis assay and cell cycle analysis. Moreover, an in-silico analysis has proposed VEGFR-2 as a probable enzymatic target for piperine-based derivatives, and then has explored the binding interactions within VEGFR-2 active site (PDB:4ASD). Finally, an in vitro VEGFR-2 inhibition assay was performed to validate the in silico findings, where 8q showed good VEGFR-2 inhibitory activity with IC50 = 231 nM.
Keywords:
Anticancer; VEGFR-2 inhibitors; molecular docking; natural products; piperic acid; triple negative breast cancer.
MeSH terms
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Alkaloids / chemistry
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Alkaloids / pharmacology*
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Benzodioxoles / chemistry
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Benzodioxoles / pharmacology*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Humans
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Molecular Structure
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Piperidines / chemistry
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Piperidines / pharmacology*
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Polyunsaturated Alkamides / chemistry
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Polyunsaturated Alkamides / pharmacology*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Urea / analogs & derivatives
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Urea / chemistry
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Urea / pharmacology*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Alkaloids
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Amides
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Antineoplastic Agents
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Benzodioxoles
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Piperidines
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Polyunsaturated Alkamides
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Protein Kinase Inhibitors
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Urea
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-2
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piperine
Grants and funding
The authors would like to extend their appreciation to the The Science, Technology & Innovation Funding Authority (STDF) in Egypt for funding this work through the project [number “RSTDG-34946”].