A series of novel molecules with pyrazolopyrimidine-4-amine core were designed and synthesized as potential cytotoxic agents over Renal Cell Carcinoma cells (UO-31). Results of cytotoxic activity against UO-31 cells showed that pyrazolopyrimidines 19 and 31 were found to be more cytotoxic than sorafenib (SOR). The cytotoxic activity of these compounds appeared to correlate with their ability to inhibit p38α MAPK which are 2.53- and 2.27- folds more potent than SOR. Moreover, results of the cell cycle analysis as well as the results of annexin-V on the (UO-31) cells showed that pyrazolopyrimidines 19 and 31 had a pro-apoptotic activity higher than SOR by 1.42- and 1.20- folds, respectively. Furthermore, compounds 19 and 31 were found to be effective in arresting the cell cycle throughout the accumulation of the cells at G2/M phase. Finally, the tested compounds decreased the TNF concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.

中文翻译：

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新型吡唑并嘧啶类药物对肾细胞癌 （UO-31 细胞） 作为 p38α 抑制剂和凋亡细胞诱导活性的设计、合成和细胞毒性筛选


设计并合成了一系列具有吡唑并嘧啶-4-胺核心的新型分子，作为肾细胞癌细胞 （UO-31） 的潜在细胞毒剂。针对 UO-31 细胞的细胞毒活性结果表明，吡唑并嘧啶 19 和 31 比索拉非尼 （SOR） 更具细胞毒性。这些化合物的细胞毒活性似乎与它们抑制 p38α MAPK 的能力相关，p38α MAPK 的效力是 SOR 的 2.53 倍和 2.27 倍。此外，细胞周期分析结果以及 （UO-31） 细胞上的膜联蛋白-V 结果显示，吡唑并嘧啶 19 和 31 的促凋亡活性分别比 SOR 高 1.42 倍和 1.20 倍。此外，发现化合物 19 和 31 在 G2/M 期细胞的整个积累过程中有效阻止细胞周期。最后，供试化合物降低了 TNF 浓度，增加了肿瘤抑制基因 p53 、 Bax/BCL-2 比值和 caspase 3/7 的表达。