期刊
BIOORGANIC CHEMISTRY
卷 95, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103461
关键词
Quinazolin-4-ones; Anticancer; EGFR; HER2; Molecular docking
资金
- National Plan for Science, Technology and Innovation (MAARIFAH)-King Abdulaziz City for Science and Technology-the Kingdom of Saudi Arabia [13-MED873-10]
- Deanship of Scientific Research at King Saud University [RG-1440-052]
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 mu M, respectively compared to sorafenib, the standard drug (IC50 2.50, 2.50, and 3.14 mu M 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 mu M). These compounds also displayed potent inhibitory activity against EGFR and HER2 kinases (IC50 0.09-0.43 and 0.15-0.33 mu M, respectively) compared to the standard drug, sorafenib (IC50 0.11 and 0.13 mu M, respectively). Likewise, compounds 1, 4, and 5 showed strong inhibitory activity against VEGFR2 (IC50 0.34, 0.28 and 0.39 mu M, respectively) compared to sorafenib (IC50 0.17 mu M). 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.
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