Novel Pyrazolo34-dpyrimidine Derivatives as Potential Antitumor Agents: Exploratory Synthesis Preliminary Structure-Activity Relationships and in Vitro Biological Evaluation

摘要

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.