title: Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors.
abstract: A novel series of 2-(3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(4-substitutedbenzylidene)acetohydrazide (12a-g) was prepared and their structures were confirmed by spectral and elemental analyses. The cytotoxic activity of the newly synthesized compounds was evaluated against breast carcinoma (MCF-7), non-small cell lung cancer (A549) and human colorectal adenocarcinoma (HT-29) cell lines using MTT and colony formation assays. The tested compounds showed a marked anticancer activity against all the tested cell lines, especially compound 12g, which was the most potent anticancer agent with half maximal inhibitory concentrations (IC50) between 5.36 and 9.09μM. Docking studies into ATP binding site of EGFR protein tyrosine kinase were performed to predict their scores and mode of binding to amino acids, In addition, the inhibitory activity of the target compounds against epidermal growth factor receptor tyrosine kinase (EGFR-TK) was evaluated. Results indicated the ability of the target compounds to inhibit EGFR-TK with half maximal inhibitory concentrations (IC50) in the range of 4.18-35.88μM. Furthermore, The most active compounds 12g, 12c and 12d were assayed against Fibroblast Growth Factor Receptor (FGFR), Insulin Receptor (IR) and Vascular Endothelial Growth Factor Receptor (VEGFR). The activity of the reported compounds warrants further optimization as novel members in cancer treatment protocols.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Al Jouf University, Sakaka, Al Jouf 2014, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faulty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: mohamed.abdelgawad@pharm.bsu.edu.eg.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelgawad
authors.affiliation: Department of Pharmaceutical Organic Chemistry, Faulty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
authors.forename: Rania B
authors.initials: RB
authors.lastname: Bakr
authors.affiliation: Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
authors.forename: Olla A
authors.initials: OA
authors.lastname: Alkhoja
authors.affiliation: Department of Pharmacology, Faulty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
authors.forename: Wafaa R
authors.initials: WR
authors.lastname: Mohamed
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
keywords: Antitumor; EGFR tyrosine kinase; Pyrazolo[3,4-d]pyrimidine; Schiff bases