University of Zagreb, Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev Trg 20, HR-10000, Zagreb, Croatia.
University of Rijeka, Department of Biotechnology, Centre for High-throughput Technologies Radmile Matejčić 2, HR-51000, Rijeka, Croatia.
Eur J Med Chem. 2019 Dec 15;184:111739. doi: 10.1016/j.ejmech.2019.111739. Epub 2019 Sep 28.
Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.
我们合成了两个系列的 6-(1,2,3-三唑基)-2,3-二苄基-L-抗坏血酸衍生物，具有羟基亚乙基（8a-8u）和亚乙基连接体（10c-10p），并评估了它们对七种恶性肿瘤细胞系的抗增殖活性和对广泛病毒的抗病毒活性。8a-8u 系列中环内酯和 1,2,3-三唑单元之间的无规卷曲间隔基对抗肿瘤活性有深远的影响。此外，在 1,2,3-三唑的 C-4 上引入长侧链，导致合成了癸基取代的 2,3-二苄基-L-抗坏血酸 8m，对乳腺癌 MCF-7 细胞具有选择性和有效的抗增殖活性，其浓度为纳摩尔级。进一步的分析表明，化合物 8m 强烈增强了缺氧诱导转录因子 1α（HIF-1α）的表达，并在一定程度上降低了一氧化氮合酶 2（NOS2）的表达，表明其在调节 HIF-1α 信号通路中的作用。对甲氧基苯基取代的衍生物 10g 显示出特定的抗巨细胞病毒（CMV）潜力，而脂肪族取代的衍生物 8l 和 8m 则具有最强但相对非特异性的抗水痘-带状疱疹（VZV）活性。
