Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt.
Bioorg Chem. 2020 Sep;102:104053. doi: 10.1016/j.bioorg.2020.104053. Epub 2020 Jun 30.
A novel series of pyrazoles and pyrazolo[1,5-a]pyrimidines bearing benzothiazole moiety were designed and synthesized. Chemical structures were confirmed by spectral data and elemental analyses. Nine compounds were selected and screened for their cytotoxic activity at the National Cancer Institute (NCI), USA against 60 cancer cell lines in a single dose assay. Compounds 4 and 5 exerted the most potent growth inhibitory activity against most cancer cell lines with growth inhibition (GI%) ranges from 44.86% to 84.59% and 31.20% to 52.36%, respectively. Consequently, they were further investigated through IC determination using five dose MTT colorimetric assay against three sensitive cell lines, leukemia CCRF-CEM, non-small cell lung cancer HOP-92 and liver cancer Hep-G2. Compound 4 exhibited potent cytotoxic activity against the three tested cell lines with IC 16.34, 3.45 and 7.79 μM, respectively representing half potency, 3.5 folds potency and nearly equipotent to roscovitine. To investigate its mechanism of action, cell cycle analysis of compound 4 was conducted and showed that it induced cell cycle arrest at G2/M phase and apoptosis in HOP-92 cells. In correlation with the previous results, caspase-3 activation was tested and illustrated elevation in its concentration by nearly 14 folds than control. Besides, enzyme inhibition assay of compound 4 was evaluated towards two common antitumor targets namely KDM1 and CDK1 showing significant inhibitory activity with IC 0.096 and 0.078 μM, respectively.
设计并合成了一系列含有苯并噻唑部分的新型吡唑和吡唑并[1,5-a]嘧啶。通过光谱数据和元素分析确认了化学结构。选择了 9 种化合物，并在美国国立癌症研究所（NCI）进行了单次剂量测定，以评估它们对 60 种癌细胞系的细胞毒性。化合物 4 和 5 对大多数癌细胞系表现出最强的生长抑制活性，生长抑制率（GI%）范围分别为 44.86%至 84.59%和 31.20%至 52.36%。因此，它们通过使用五种剂量 MTT 比色法对三种敏感细胞系（白血病 CCRF-CEM、非小细胞肺癌 HOP-92 和肝癌 Hep-G2）进行 IC 测定进一步进行了研究。化合物 4 对三种测试细胞系表现出强烈的细胞毒性活性，IC 50 值分别为 16.34、3.45 和 7.79 μM，分别代表半效、3.5 倍效和几乎与罗西维汀等效。为了研究其作用机制，对化合物 4 进行了细胞周期分析，结果表明它在 HOP-92 细胞中诱导细胞周期停滞在 G2/M 期和细胞凋亡。与先前的结果相关，测试了化合物 4 对 caspase-3 的激活作用，并表明其浓度比对照升高近 14 倍。此外，还评估了化合物 4 对两种常见抗肿瘤靶标 KDM1 和 CDK1 的酶抑制活性，IC 50 值分别为 0.096 和 0.078 μM，显示出显著的抑制活性。
