Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey.
Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey; Drug Application and Research Center, Erciyes University, 38039 Kayseri, Turkey.
Bioorg Med Chem. 2021 May 1;37:116097. doi: 10.1016/j.bmc.2021.116097. Epub 2021 Mar 13.
Naproxen is a common non-steroidal anti-inflammatory drug, which is the most usually used propionic acid derivative for the treatment of many types of diseases. In this study, a series of novel (S)-Naproxen derivatives bearing hydrazide-hydrazone moiety were designed, synthesized, and evaluated for anticancer activity. The structures of these compounds were characterized by spectral (H-C NMR, FT-IR, and HR-MS analyses) methods. All synthesized compounds were screened for anticancer activity against two different human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, (S)-2-(6-methoxynaphthalen-2-yl)-N'-{(E)-[2-(trifluoromethoxy)phenyl]methylidene} propanehydrazide (3a) showed the most potent anticancer activity against both cancer cell lines with a good selectivity (IC = 22.42 and 59.81 µM, respectively). Furthermore, the molecular modeling of these compounds was studied on Vascular Endothelial Growth Factor Receptor 2. Inhibition of VEGFR-2 and apoptotic protein Bcl-2 was investigated in MDA-MB-231 cells treated with compound 3a by using Western Blotting. Apoptosis was also detected by staining with DAPI in fluorescence microscopy. Flow Cytometry analyses related to cell cycle phases showed that a dramatic increase in S and M phases was established compared to untreated control cells indicating the cancer cell cycle arrest. The anticancer activity of compound 3a was investigated in the Ehrlich acid tumor model, a well-validated in vivo ectopic breast cancer model, in mice. Our results showed that compound 3a had anticancer activity and decreased the tumor volume in both low (60 mg/kg) and high (120 mg/kg) doses in mice.
萘普生是一种常见的非甾体抗炎药，是治疗多种疾病最常用的丙酸衍生物。在这项研究中，设计、合成了一系列含有酰腙结构的新型（S）-萘普生衍生物，并对其进行了抗癌活性评价。这些化合物的结构通过光谱（H-C NMR、FT-IR 和 HR-MS 分析）方法进行了表征。所有合成的化合物都进行了抗两种不同的人乳腺癌细胞系（MDA-MB-231 和 MCF-7）的抗癌活性筛选。其中，（S）-2-（6-甲氧基萘-2-基）-N'-{（E）-[2-（三氟甲氧基）苯基]亚甲基}丙烷酰腙（3a）对两种癌细胞系均表现出最强的抗癌活性，且具有良好的选择性（IC = 22.42 和 59.81 μM）。此外，还对这些化合物进行了血管内皮生长因子受体 2 的分子建模研究。通过 Western Blotting 研究了化合物 3a 处理 MDA-MB-231 细胞后对 VEGFR-2 和凋亡蛋白 Bcl-2 的抑制作用。通过荧光显微镜用 DAPI 染色检测凋亡。与细胞周期相关的流式细胞术分析表明，与未处理的对照细胞相比，S 和 M 期明显增加，表明癌细胞周期停滞。在埃利希腹水肿瘤模型（一种经过充分验证的体内异位乳腺癌模型）中研究了化合物 3a 的抗癌活性，该模型在小鼠中进行。我们的结果表明，化合物 3a 具有抗癌活性，并在低（60 mg/kg）和高（120 mg/kg）剂量下均可降低小鼠的肿瘤体积。
