Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
Bioorg Chem. 2020 Dec;105:104352. doi: 10.1016/j.bioorg.2020.104352. Epub 2020 Oct 8.
PDE5 targeting represents a new and promising strategy for apoptosis induction and inhibition of tumor cell growth due to its over-expression in diverse types of human carcinomas. Accordingly, we report the synthesis of series of pyrazolo[3,4-d]pyrimidin-4-one carrying quinoline moiety (11a-r) with potential dual PDE5 inhibition and apoptotic induction for cancer treatment. These hybrids were structurally elucidated and characterized with variant spectroscopic techniques as H NMR, C NMR and elemental analysis. The assessment of their anticancer activities has been declared. All the rationalized compounds 11a-r have been selected for their cytotoxic activity screening by NCI against 60 cell lines. Compounds 11a, 11b, 11j and 11k were the most active hybrids. Among all, compound 11j was further selected for five dose tesing and it displayed outstanding activity with strong antitumor activity against the nine tumor subpanels tested with selectivity ratios ranging from 0.019 to 8.3 at the GI level. Further, the most active targets 11a, b, j and k were screened for their PDE5 inhibitory activity, compound 11j (with IC 1.57 nM) exhibited the most potent PDE5 inhibitory activity. Moreover, compound 11j is also showed moderate EGFR inhibition with IC of 5.827 ± 0.46 µM, but significantly inhibited the Wnt/β-catenin pathway with IC1286.96 ± 12.37 ng/mL. In addition, compound 11j induced the intrinsic apoptotic mitochondrial pathway in HepG2 cells as evidenced by the lower expression levels of the anti-apoptotic Bcl-2 protein, and the higher expression of the pro-apoptotic protein Bax, p53, cytochrome c and the up-regulated active caspase-9 and caspase-3 levels. All results confirmed by western blotting assay. Compound 11j exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase. In conclusion, hybridization of quinoline moiety with the privileged pyrazolo[3,4-d]pyrimidinon-4-one structure resulted in highly potent anticancer agent, 11j, which deserves more study, in particular, in vivo and clinical investiagtions, and it is expected that these results would be applied for more drug discovery process.
PDE5 靶向治疗代表了一种新的有前途的策略，可诱导细胞凋亡并抑制肿瘤细胞生长，因为它在多种人类癌中过度表达。因此，我们报告了一系列带有喹啉部分的吡唑并[3,4-d]嘧啶-4-酮（11a-r）的合成，这些化合物具有潜在的双重 PDE5 抑制作用和诱导细胞凋亡作用，可用于癌症治疗。这些混合物的结构通过各种光谱技术进行了阐明和表征，包括 H NMR、C NMR 和元素分析。评估了它们的抗癌活性。根据 NCI 对 60 种细胞系的细胞毒性活性筛选，对所有合理化化合物 11a-r 进行了筛选。化合物 11a、11b、11j 和 11k 是最活跃的混合物。在所有化合物中，化合物 11j 进一步进行了五个剂量测试，它对所测试的 9 个肿瘤亚群表现出出色的活性，选择性比率范围从 GI 水平的 0.019 到 8.3。此外，对最活跃的靶标 11a、b、j 和 k 进行了 PDE5 抑制活性筛选，化合物 11j（IC 1.57 nM）表现出最强的 PDE5 抑制活性。此外，化合物 11j 还表现出对 EGFR 的中等抑制作用，IC 为 5.827 ± 0.46 μM，但对 Wnt/β-catenin 途径具有显著抑制作用，IC1286.96 ± 12.37 ng/mL。此外，化合物 11j 在 HepG2 细胞中诱导了内在的凋亡线粒体途径，这表现在抗凋亡 Bcl-2 蛋白的表达水平降低，以及促凋亡蛋白 Bax、p53、细胞色素 c 和活性 caspase-9 和 caspase-3 水平的上调。所有结果均通过 Western blot 检测得到证实。化合物 11j 表现出预 G1 凋亡和 G2/M 期细胞周期停滞。总之，将喹啉部分与优势吡唑并[3,4-d]嘧啶-4-酮结构进行杂交得到了高度有效的抗癌剂 11j，值得进一步研究，特别是在体内和临床研究中，我们希望这些结果将应用于更多的药物发现过程。
