Radwan Rasha R, Zaher Nashwa H, El-Gazzar Marwa G
Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), P.O. Box 29, Nasr City, Cairo, Egypt.
Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), P.O. Box 29, Nasr City, Cairo, Egypt.
Chem Biol Interact. 2017 Aug 25;274:68-79. doi: 10.1016/j.cbi.2017.07.008. Epub 2017 Jul 8.
Fifteen novel 1,2,3-triazole derivatives were prepared in series of synthetic steps starting from 4-amino-5-hydrazino-4H-1,2,4-triazole-3-thiol 1. The structures of the obtained compounds were verified through micoanalytical and spectral data. All the compounds were screened for their anticancer activity against liver human cancer cell lines (HEPG2) using Doxorubicin as standard. The most promising triazolothiadiazine derivative 12 was further tested for its degree of toxicity by estimating the median lethal dose (LD 50) and its antitumor activity through inhibiting the angiogenesis and progression of tumor against diethylnitrosamine (DENA)/CCl induced hepatocellular carcinoma (HCC) in rats. To elucidate its mechanism of action, the following parameters were determined including: vascular endothelial growth factor (VEGF) as a marker of angiogenesis; hepatic tyrosine kinase (HTK) as a marker for tumor growth; serum alpha fetoprotein (AFP) as a marker for hepatocarcinoma; aspartate and alanine aminotransferases (AST & ALT) as liver function test; malondialdehyde (MDA) and glutathione (GSH) as markers of antioxidant activity. Liver histopathological analysis was also evaluated. Carcinogenic rats showed drastic elevation in all investigated parameters accompanied by reduction in hepatic glutathione. Administration of compound 12 into rats after induction of experimental HCC, improved the biochemical changes induced by DENA/CCl. These observations were supported by histopathological study of liver sections. It was concluded that triazolothiadiazine compound 12 could be promising anti HCC agent after more investigations on higher animals.
以4-氨基-5-肼基-4H-1,2,4-三唑-3-硫醇1为起始原料，通过一系列合成步骤制备了15种新型1,2,3-三唑衍生物。通过微量分析和光谱数据对所得化合物的结构进行了验证。以阿霉素为标准，对所有化合物针对人肝癌细胞系（HEPG2）的抗癌活性进行了筛选。通过估计半数致死剂量（LD50）进一步测试了最有前景的三唑并噻二嗪衍生物12的毒性程度，并通过抑制二乙基亚硝胺（DENA）/四氯化碳诱导的大鼠肝细胞癌（HCC）的血管生成和肿瘤进展来评估其抗肿瘤活性。为阐明其作用机制，测定了以下参数：血管内皮生长因子（VEGF）作为血管生成的标志物；肝酪氨酸激酶（HTK）作为肿瘤生长的标志物；血清甲胎蛋白（AFP）作为肝癌的标志物；天冬氨酸和丙氨酸转氨酶（AST和ALT）作为肝功能测试指标；丙二醛（MDA）和谷胱甘肽（GSH）作为抗氧化活性的标志物。还对肝脏进行了组织病理学分析。致癌大鼠所有研究参数均显著升高，同时肝谷胱甘肽减少。在实验性肝癌诱导后给大鼠施用化合物12，改善了DENA/CCl诱导的生化变化。肝脏切片的组织病理学研究支持了这些观察结果。得出的结论是，在对高等动物进行更多研究后，三唑并噻二嗪化合物12有望成为抗肝癌药物。
