Synthesis, anticancer and apoptosis-inducing activities of quinazoline-isatin conjugates: epidermal growth factor receptor-tyrosine kinase assay and molecular docking studies

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 32; no. 1; pp. 935 - 944
• Main Authors: El-Azab, Adel S., Al-Dhfyan, Abdullah, Abdel-Aziz, Alaa A.-M., Abou-Zeid, Laila A., Alkahtani, Hamad M., Al-Obaid, Abdulrahman M., Al-Gendy, Manal A.
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2017; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: 5-Fluorouracil; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor; Antitumor activity; Antitumor agents; Apoptosis; Apoptosis - drug effects; Biochemistry & Molecular Biology; Breast cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Colon cancer; Cytotoxicity; Drug Screening Assays, Antitumor; EGFR-TK; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Humans; isatin; Isatin - chemistry; Isatin - pharmacology; Kinases; Life Sciences & Biomedicine; molecular docking; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Protein-tyrosine kinase; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolinone; Science & Technology; Structure-Activity Relationship; Synthesis; EGFR-TK; DESIGN; antitumor; ANALOGS; ANTITUMOR-ACTIVITY; isatin; ANTICONVULSANT EVALUATION; SU11248; SUBSTITUTED QUINAZOLINES; Synthesis; molecular docking; quinazolinone; BIOLOGICAL EVALUATION; INHIBITOR; DERIVATIVES; ZD1839
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2017.1344981

A new series of quinazolinone compounds 16-34 incorporating isatin moieties was synthesized. The antitumor efficacy of the compounds against MDA-MB-231, a breast cancer cell line, and LOVO, a colon cancer cell line, was assessed. Compounds 20, 21, 22, 23, 25, 27, 28, 29, 30, 31, 32, 33, and 34 displayed potent antitumor activity against MDA-MB-231 and LOVO cells (IC 50 : 10.38-38.67 μM and 9.91-15.77 μM, respectively); the comparative IC 50 values for 5-fluorouracil and erlotinib in these cells lines were 70.28 μM, 22.24 μM and 15.23 μM, 25.31 μM respectively. The EGFR-TK assay and induction of apoptosis for compound 31 were investigated to assess its potential cytotoxic activity as a representative example of the novel synthesized compounds. At a concentration of 10 μM, compound 31 exhibited efficient inhibitory effect against EGFR-TK and induced apoptosis in MDA-MB-231 cells. Furthermore, a molecular docking study for compound 31 and erlotinib was performed to verify the binding mode toward the EGFR kinase enzyme, and showed a similar interaction as that with erlotinib alone. Graphical Abstract: Compound 31 showed potent antitumor activity and efficient inhibitory effect against EGFR-TK and induced apoptosis of MDA-MB-231 cells at a concentration of 10 μM.