Shaaban Saad, Negm Amr, Sobh Mohamed A, Wessjohann Ludger A
Organic Chemistry Division, Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhorya Street, 35516 Mansoura, Egypt; Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
Biochemistry Division, Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhorya Street, 35516 Mansoura, Egypt.
Eur J Med Chem. 2015 Jun 5;97:190-201. doi: 10.1016/j.ejmech.2015.05.002. Epub 2015 May 4.
Oxidative stress (OS) and disturbed intracellular redox balance have been predominantly observed in different types of cancer, including hepatocellular carcinoma (HCC). Agents which can stop OS multi-stressor events and modulate the intracellular redox state are becoming a major focus in HCC prevention. Among them, compounds with glutathione peroxidase (GPx)-like activity are of particularly concern. We herein report the synthesis of novel series of organoselenocyanates and symmetrical diselenide antioxidants, inspired by the natural redox enzyme, GPx and the synthetic organoselenium ebselen antioxidants. Their cytotoxic activity was evaluated against Hep G2 cells and their antimicrobial activities were evaluated against Candida albicans (C. albicans) fungus as well as against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), gram-negative and gram-positive bacteria, respectively. These compounds were also tested for their antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), GPx-like activity and bleomycin dependent DNA damage assays and a basic structure-activity relationship was subsequently established. The physicochemical parameters and drug-likeness were computed employing the Molinspiration online property calculation toolkit and MolSoft software. Interestingly, some compounds proved to be more cytotoxic than ebselen and the known anticancer drug 5-Fu and in the same time they showed similar, sometime even more, antifungal activity than the reference antifungal drugs. Among these compounds, compound 16 was considered to be the most interesting with free radical-scavenging activity comparable to ascorbic acid and a GPx-like activity similar to ebselen. As most of these compounds comply with Lipinski's Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.
氧化应激（OS）和细胞内氧化还原平衡紊乱在包括肝细胞癌（HCC）在内的不同类型癌症中普遍存在。能够阻止OS多应激事件并调节细胞内氧化还原状态的药物正成为HCC预防的主要焦点。其中，具有谷胱甘肽过氧化物酶（GPx）样活性的化合物尤其受到关注。我们在此报告了一系列新型有机硒氰酸盐和对称二硒化物抗氧化剂的合成，其灵感来源于天然氧化还原酶GPx和合成有机硒依布硒啉抗氧化剂。评估了它们对Hep G2细胞的细胞毒性活性，并分别评估了它们对白色念珠菌（白色念珠菌）真菌以及革兰氏阴性菌大肠杆菌（大肠杆菌）和革兰氏阳性菌金黄色葡萄球菌（金黄色葡萄球菌）的抗菌活性。还使用2,2-二苯基-1-苦基肼基（DPPH）、GPx样活性和博来霉素依赖性DNA损伤试验测试了这些化合物的抗氧化活性，并随后建立了基本的构效关系。使用Molinspiration在线性质计算工具包和MolSoft软件计算了物理化学参数和药物相似性。有趣的是，一些化合物被证明比依布硒啉和已知抗癌药物5-氟尿嘧啶具有更强的细胞毒性，同时它们显示出与参考抗真菌药物相似，有时甚至更强的抗真菌活性。在这些化合物中，化合物16被认为是最有趣的，其自由基清除活性与抗坏血酸相当，GPx样活性与依布硒啉相似。由于这些化合物中的大多数符合Lipinski的五规则，它们有望具有良好的生物利用度，这需要作为未来研究的一部分进行研究。
