Anticancer potential of novel symmetrical and asymmetrical dihydropyridines against breast cancer via EGFR inhibition: molecular design, synthesis, analysis and screening.

Autor: Faizan S; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Constituent College of JSS Academy of Higher Education & Research Mysuru 570015 India brprashanthkumar@jssuni.edu.in +91-821-2548359 +91-821-2548353., Talath S; Department of Pharmaceutical Chemistry, RAK Medical & Health Sciences University Ras Al Khaimah UAE., Wali AF; Department of Pharmaceutical Chemistry, RAK Medical & Health Sciences University Ras Al Khaimah UAE., Hani U; Department of Pharmaceutics, College of Pharmacy, King Khalid University Abha Saudi Arabia., Haider N; Department of Pathology, College of Medicine, King Khalid University Abha Saudi Arabia., Mandal SP; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Constituent College of JSS Academy of Higher Education & Research Mysuru 570015 India brprashanthkumar@jssuni.edu.in +91-821-2548359 +91-821-2548353., Kumar BRP; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Constituent College of JSS Academy of Higher Education & Research Mysuru 570015 India brprashanthkumar@jssuni.edu.in +91-821-2548359 +91-821-2548353.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2024 Apr 09; Vol. 14 (16), pp. 11368-11387. Date of Electronic Publication: 2024 Apr 09 (Print Publication: 2024).
DOI: 10.1039/d4ra01424c
Abstrakt: A series of novel symmetrical and asymmetrical dihydropyridines (HD 1-15) were designed, subjected to in silico ADMET prediction, synthesized, analyzed by IR, NMR, Mass analytical techniques and evaluated against epidermal growth factor receptor (EGFR) as inhibitors against Breast cancer. The results of predicted ADMET studies demonstrated the drug-likeness properties of the reported compounds. The in vitro cytotoxicity assessment of the synthesized compounds revealed that all of them showed good activity (IC 50 ranging from 16.75 to 66.54 μM) towards MCF-7 breast cancer cells compared to the standard drug, Lapatinib (IC 50 = 2.02 μM). Among these, compounds HD-6, HD-7, and HD-8 displayed the most potent activity with IC 50 value of 21.26, 16.75, and 18.33 μM, respectively. Cytotoxicity of all compounds was tested on normal vero cells for comparison at different concentrations using the MTT assay. In addition to the MTT assay, the potent dihydropyridines derivatives were screened for EGFR wt kinase inhibition assay at concentrations ranging from 1 nM to 360 nM. Among the three compounds tested, HD-8 showed reasonably good inhibition with an IC 50 value of 15.90 ± 1.20 nM compared to a standard Lapatinib IC 50 value of 10.28 ± 1.01 nM. Based on the molecular docking study against EGFR, the most active derivatives HD-7 and HD-8 were docked against the active site of the protein and showed better binding affinity than the standard lapatinib. Additionally, molecular dynamics (MD) simulations were performed to explore the stability of the protein-ligand complex, its dynamic behavior, and the binding affinity.
Competing Interests: The authors declare no financial conflicts of interest or personal affiliations that could have influenced the research conducted in this study.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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