Novel pyrazolo[3,4-d]pyrimidine derivatives as potential antitumor agents: exploratory synthesis, preliminary structure-activity relationships, and in vitro biological evaluation

• Published in: Molecules (Basel, Switzerland) Vol. 16; no. 12; pp. 10685 - 10694
• Main Authors: He, Hai-Yun, Zhao, Jin-Ni, Jia, Ruo, Zhao, Ying-Lan, Yang, Sheng-Yong, Yu, Luo-Ting, Yang, Li
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.12.2011; MDPI
• Subjects: anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; exploratory synthesis; Humans; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; pyrazolo[3,4-d]pyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; China
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules161210685

In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC₅₀ for A549 cells was 2.24 µM, compared with an IC₅₀ of 9.20 µM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies.