Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors

Mohamed A Abdelgawad; Rania B Bakr; Olla A Alkhoja; Wafaa R Mohamed

doi:10.1016/j.bioorg.2016.03.011

Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors

Bioorg Chem. 2016 Jun:66:88-96. doi: 10.1016/j.bioorg.2016.03.011. Epub 2016 Mar 24.

Authors

Mohamed A Abdelgawad¹, Rania B Bakr², Olla A Alkhoja³, Wafaa R Mohamed⁴

Affiliations

¹ 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.
² Department of Pharmaceutical Organic Chemistry, Faulty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
³ Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
⁴ Department of Pharmacology, Faulty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.

PMID: 27043178
DOI: 10.1016/j.bioorg.2016.03.011

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.

Keywords: Antitumor; EGFR tyrosine kinase; Pyrazolo[3,4-d]pyrimidine; Schiff bases.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
ErbB Receptors