Ross Christina R, Temburnikar Kartik W, Wilson Gerald M, Seley-Radtke Katherine L
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
Bioorg Med Chem Lett. 2015 Apr 15;25(8):1715-1717. doi: 10.1016/j.bmcl.2015.02.071. Epub 2015 Mar 7.
Halogenated thieno[3,2-d]pyrimidines exhibit antiproliferative activity against a variety of cancer cell models, such as the mouse lymphocytic leukemia cell line L1210 in which they induce apoptosis independent of cell cycle arrest. Here we assessed these activities on MDA-MB-231 cells, a well-established model of aggressive, metastatic breast cancer. While 2,4-dichloro[3,2-d]pyrimidine was less toxic to MDA-MB-231 cells than previously observed in the L1210 model, flow cytometry analysis showed that MDA-MB-231 cell death involved arrest at the G2/M stage of the cell cycle. Conversely, the introduction of bromine at C7 of the 2,4-dichloro[3,2-d]pyrimidine eliminated cell type-dependent differences in cytotoxicity or cell cycle status. Together, these data indicate that a substituent at C7 can profoundly modify the cytotoxic mechanism of halogenated thieno[3,2-d]pyrimidines in a cell type-specific manner.
卤代噻吩并[3,2 - d]嘧啶对多种癌细胞模型具有抗增殖活性，例如小鼠淋巴细胞白血病细胞系L1210，在该细胞系中它们可诱导凋亡，且与细胞周期停滞无关。在此，我们评估了这些化合物对MDA - MB - 231细胞的活性，MDA - MB - 231细胞是侵袭性转移性乳腺癌的一个成熟模型。虽然2,4 - 二氯[3,2 - d]嘧啶对MDA - MB - 231细胞的毒性低于先前在L1210模型中观察到的毒性，但流式细胞术分析表明，MDA - MB - 231细胞死亡涉及细胞周期在G2/M期的停滞。相反，在2,4 - 二氯[3,2 - d]嘧啶的C7位引入溴消除了细胞毒性或细胞周期状态方面的细胞类型依赖性差异。总之，这些数据表明C7位的取代基能够以细胞类型特异性方式深刻改变卤代噻吩并[3,2 - d]嘧啶的细胞毒性机制。
