Garnica Pablo, Encío Ignacio, Plano Daniel, Palop Juan A, Sanmartín Carmen
University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry, Irunlarrea 1, E-31008 Pamplona, Spain.
Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain.
ACS Med Chem Lett. 2018 Mar 13;9(4):306-311. doi: 10.1021/acsmedchemlett.7b00482. eCollection 2018 Apr 12.
A series of 16 new diselenide-acylselenourea conjugates have been designed following the fragment-based drug strategy. Compound cytotoxic potential was evaluated against six human cancer cell lines and two nonmalignant derived cell lines with the aim of determining their potency and selectivity. Nine derivatives exhibited GI values under 10 μM in at least four cancer cell lines. A clear gap situated phenyl substitution over heterocyclic moieties in terms of selectivity. Among carbocyclic compounds, derivatives and significantly inhibited cell growth of breast adenocarcinoma cells with GI values of 1.30 and 0.15 nM, respectively, with selectivity indexes 12 and 121 times higher than those obtained for doxorubicin. Preliminary mechanistic studies indicated that compounds and induce cell cycle arrest and autophagy-dependent cell death evidenced by the blockage of cell death with pretreatment with wortmannin or chloroquine and confirmed by the upregulation of the markers Beclin1 and LC3B in MCF-7 cells.
按照基于片段的药物策略设计了一系列16种新的二硒化物-酰基硒脲缀合物。评估了化合物对六种人类癌细胞系和两种非恶性来源细胞系的细胞毒性潜力，目的是确定它们的效力和选择性。九种衍生物在至少四种癌细胞系中的GI值低于10μM。在选择性方面，苯环取代在杂环部分上存在明显差异。在碳环化合物中，衍生物 和 分别以1.30和0.15 nM的GI值显著抑制乳腺腺癌细胞的生长，其选择性指数分别比阿霉素高12倍和121倍。初步机制研究表明，化合物 和 诱导细胞周期停滞和自噬依赖性细胞死亡，用渥曼青霉素或氯喹预处理可阻断细胞死亡，在MCF-7细胞中Beclin1和LC3B标志物的上调证实了这一点。
