Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt.
Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt.
Bioorg Chem. 2021 Dec;117:105424. doi: 10.1016/j.bioorg.2021.105424. Epub 2021 Oct 15.
A new series of N-(2-((4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine sulfonamide derivatives 11a-o were designed and synthesized based on our previous works. The new series was tested for its anticancer and anti-inflammatory effects. The anticancer profile of final target compounds was obtained by testing them over 60 cell lines belong to nine types of cancers. Compound 11c showed the highest percent inhibition, so its potency was measured over the most sensitive cell line to determine its IC over each cell. In addition, compound 11c was tested over kinase panel to get its biological target(s). Compound 11c had strong activity over JNK1, JNK2, p38a and V600EBRAF. All final target compounds were tested against the four kinases to build a structure activity relationship. Compound 11c was subjected to cell cycle analysis to check at which phase is affected by 11c. The anti-inflammatory effect of final target compounds was screened by testing their ability to inhibit both nitric oxide release and prostaglandin E2 production on raw 264.7 macrophages in addition to test their cytotoxic effect on the same cells. Compound 11n showed the highest ability to inhibit prostaglandin E2 and all compound showed moderate to low activity regarding inhibition of nitric oxide release. Compound 11n was investigated for its ability to reduce Interleukin 6 and TNF-alpha. In addition, compound 11n was tested for its effect on induced Nitric oxide synthase (iNOS), and COX-2 mRNA expression level and its effect on nitric oxide synthase (iNOS), COX-1 and COX-2 protein levels where it showed selectivity for COX-2 compared to COX-1 and iNOS.
基于我们之前的工作，设计并合成了一系列新的 N-(2-((4-(1,3-二苯基-1H-吡唑-4-基)吡啶磺酰胺衍生物 11a-o。通过对 60 多种属于九种癌症类型的细胞系进行测试，获得了最终目标化合物的抗癌谱。化合物 11c 显示出最高的抑制百分比，因此对最敏感的细胞系进行了其效力测试，以确定其在每个细胞上的 IC。此外，还对化合物 11c 进行了激酶谱测试，以确定其生物靶标。化合物 11c 在 JNK1、JNK2、p38a 和 V600EBRAF 上具有很强的活性。所有最终目标化合物都在四个激酶上进行了测试，以建立构效关系。对化合物 11c 进行细胞周期分析，以检查 11c 影响哪个阶段。通过测试它们抑制 RAW 264.7 巨噬细胞中一氧化氮释放和前列腺素 E2 产生的能力，以及测试它们对同一细胞的细胞毒性作用，筛选最终目标化合物的抗炎作用。化合物 11n 显示出抑制前列腺素 E2 的最高能力，所有化合物在抑制一氧化氮释放方面表现出中等至低活性。研究了化合物 11n 降低白细胞介素 6 和肿瘤坏死因子-α的能力。此外，还测试了化合物 11n 对诱导型一氧化氮合酶 (iNOS) 的影响以及 COX-2 mRNA 表达水平及其对一氧化氮合酶 (iNOS)、COX-1 和 COX-2 蛋白水平的影响，结果表明它对 COX-2 具有选择性，而对 COX-1 和 iNOS 则没有选择性。
