Synthesis, cytotoxic evaluation, and molecular docking studies of novel quinazoline derivatives with benzenesulfonamide and anilide tails: Dual inhibitors of EGFR/HER2

Compounds 1–5 exhibited potent HER2 inhibitory activity (IC50 = 0.15–0.33 μM). In addition, this was accompanied by potent antiproliferative activity against the breast cancer cell line MCF-7 (IC50 = 0.65–3.86 μM). [Display omitted] We synthesized a new series of 2-[(3-(4-sulfamoylphenethyl)-4(3H)-q...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic chemistry 2020-01, Vol.95, p.103461, Article 103461
Main Authors: Alkahtani, Hamad M., Abdalla, Ashraf N., Obaidullah, Ahmad J., Alanazi, Mohammed M., Almehizia, Abdulrahman A., Alanazi, Mashael G., Ahmed, Ahmed Y., Alwassil, Osama I., Darwish, Hany W., Abdel-Aziz, Alaa A.-M., El-Azab, Adel S.
Format: Article
Language:English
Subjects:
Anilides - chemistry
Anilides - pharmacology
Anticancer
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Benzenesulfonamides
Cell Line, Tumor
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
EGFR
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - metabolism
HER2
Humans
Molecular docking
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Quinazolin-4-ones
Quinazolines - chemical synthesis
Quinazolines - chemistry
Quinazolines - pharmacology
Receptor, ErbB-2 - antagonists & inhibitors
Receptor, ErbB-2 - metabolism
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonamides - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Compounds 1–5 exhibited potent HER2 inhibitory activity (IC50 = 0.15–0.33 μM). In addition, this was accompanied by potent antiproliferative activity against the breast cancer cell line MCF-7 (IC50 = 0.65–3.86 μM). [Display omitted] We synthesized a new series of 2-[(3-(4-sulfamoylphenethyl)-4(3H)-quinazolinon-2-yl)thio]anilide derivatives (2–16) and evaluated their cytotoxic activity against breast adenocarcinoma (MCF-7), colorectal adenocarcinoma (HT-29), and acute myeloid leukemia (HL-60 and K562) cells. To reveal their selectivity toward cancer cells, the compounds were also tested against the human fibroblast cell line, MRC-5. Compounds 1–5 exhibited potent cytotoxic activity against the tested cell lines with IC50 values of 0.65–3.86, 0.68–4.60, 0.41–1.45, 0.42–4.07, and 3.77–25.55 μM, respectively compared to sorafenib, the standard drug (IC50 2.50, 2.50, and 3.14 μM against MCF-7, HT-29, and HL60 cells, respectively). Interestingly, compounds 1–5 displayed selectivity toward the cancer cell lines over MRC-5 (IC50 3.77–25.55 μM). These compounds also displayed potent inhibitory activity against EGFR and HER2 kinases (IC50 0.09–0.43 and 0.15–0.33 μM, respectively) compared to the standard drug, sorafenib (IC50 0.11 and 0.13 μM, respectively). Likewise, compounds 1, 4, and 5 showed strong inhibitory activity against VEGFR2 (IC50 0.34, 0.28 and 0.39 μM, respectively) compared to sorafenib (IC50 0.17 μM). We also employed molecular docking to identify the structural features required for the EGFR/HER2 inhibitory activity of the new series. Ultimately, compounds 1, 4, and 5 were demonstrated to be candidates for further preclinical investigations.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2019.103461