Alcolea Verónica, Plano Daniel, Encío Ignacio, Palop Juan Antonio, Sharma Arun K, Sanmartín Carmen
Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain.
Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain; Department of Pharmacology, Penn State Hershey Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Eur J Med Chem. 2016 Nov 10;123:407-418. doi: 10.1016/j.ejmech.2016.07.042. Epub 2016 Jul 21.
In this work, 27 novel hybrid derivatives containing diverse substituents with chalcogen atoms (selenium or sulfur) and several active heterocyclic scaffolds have been synthesized. Compounds were tested against two human cancer cells lines (MCF7 and PC-3) and a normal human mammary epithelial cell line (184B5) in order to determine their activity and selectivity against malignant cells. Ten compounds showed GI50 values below 10 μM in at least one of the cancer cell lines and six of them exhibited a selectivity index higher than 9. In general, selenium-containing compounds were more active than their corresponding sulfur analogs but we found some thiocyanate derivatives with comparable or higher activity and selectivity. Among the different substituents, the seleno- and thio-cyanate groups showed the most promising results. On the basis of their potent activity and high selectivity index, compounds 7e and 8f (containing a thiocyanate and a selenocyanate group, respectively) were selected for further biological evaluation. Both the compounds induced caspase-dependent cell death and cell cycle arrest in G2/M phase. In addition, these compounds do not violate any of the Lipinski's Rule of Five and thus possess good potential to become drugs, compound 7e being particularly promising.
在本研究中，已合成了27种新型杂化衍生物，这些衍生物含有带有硫属原子（硒或硫）的不同取代基以及几种活性杂环骨架。为了确定化合物对恶性细胞的活性和选择性，对两种人类癌细胞系（MCF7和PC-3）和一种正常人类乳腺上皮细胞系（184B5）进行了测试。十种化合物在至少一种癌细胞系中显示出低于10 μM的GI50值，其中六种化合物的选择性指数高于9。一般来说，含硒化合物比其相应的硫类似物更具活性，但我们发现一些硫氰酸盐衍生物具有相当或更高的活性和选择性。在不同的取代基中，硒氰酸酯和硫氰酸酯基团显示出最有前景的结果。基于其强大的活性和高选择性指数，选择化合物7e和8f（分别含有硫氰酸酯和硒氰酸酯基团）进行进一步的生物学评估。这两种化合物均诱导了依赖半胱天冬酶的细胞死亡和G2/M期的细胞周期阻滞。此外，这些化合物均未违反任何Lipinski五规则，因此具有成为药物的良好潜力，化合物7e尤其有前景。
