State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
Molecules. 2011 Dec 20;16(12):10685-94. 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.
在一项新型抗癌药物的基于细胞的筛选中，具有吡唑并[3,4-d]嘧啶骨架的候选化合物 1a 表现出对四种不同类型肿瘤细胞系的高抑制活性。特别是，化合物 1a 对 A549 细胞的 IC₅₀ 为 2.24 µM，而阳性对照多柔比星的 IC₅₀ 为 9.20 µM。探索了关键中间体 3 的四种合成路线，并通过路线 D 在克级规模上制备了 1a 以进行进一步研究。合成了 1a 的两个类似物，并研究了它们的初步结构-活性关系。流式细胞术分析表明，化合物 1a 在低微摩尔浓度下可显著诱导 A549 细胞体外凋亡。这些结果表明，靶化合物 1a 及其具有吡唑并[3,4-d]嘧啶骨架的类似物可能潜在构成一类新型抗癌药物，这需要进一步研究。
