4-Substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine Derivatives: Design, Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

• Published in: Chemical biology & drug design Vol. 85; no. 5; pp. 608 - 622
• Main Authors: Abbas, Safinaz E.-S., Aly, Enayat I., Awadallah, Fadi M., Mahmoud, Walaa R.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-05-2015
• Subjects: 4-d]pyrimidines; Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor; Binding Sites; Cell Line, Tumor; Cell Survival - drug effects; EGFR-TK inhibition; Enzyme Activation - drug effects; Humans; Hydrogen Bonding; MCF-7 Cells; Molecular Docking Simulation; molecular modeling; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Structure, Tertiary; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; pyrazolo; pyrazolo[3,4‐d]pyrimidines; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Structure-Activity Relationship; synthesis; synthesis; pyrazolo[3,4-d]pyrimidines; EGFR-TK inhibition; antitumor; molecular modeling
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12451

Four series of some 4‐substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine derivatives 5a–f, 6a–f, 8a–f, and 9a–f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF‐7) and lung (A‐549) cell lines. Six compounds 5a, 5b, 6b, 6e, 9e, and 9f displaying activity against both cell lines were further estimated for their EGFR‐TK inhibitory activity where they revealed 41–91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP‐binding site of EGFR‐TK demonstrated their binding mode where H‐bonding interaction with Met793 through N1 of pyrimidine or N2 of pyrazole was observed.
Four series of compounds comprising the pyrazolo[3,4‐d]pyrimidine core substituted at position 4 with various heterocyclic substitutions were synthesized. Antitumor activity and EGFR‐TK inhibition were evaluated.