Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.
Martin-Luther-University Halle-Wittenberg, Department of Radiotherapy, Ernst-Grube-Str. 40, D-06120 Halle (Saale), Germany.
Bioorg Chem. 2018 Dec;81:567-576. doi: 10.1016/j.bioorg.2018.09.014. Epub 2018 Sep 11.
Isocyanide-based multicomponent reactions - especially the standard four component Ugi reaction - provide an easy and powerful access to compounds with an auspicious pharmacological potential. Therefore, a set of 16 novel derivatives of the diterpene dehydroabietylamine was synthesized by the Ugi-4CR. The subsequent screening of the synthesized α-acylamino carboxamides in colorimetric sulforhodamine B assays revealed an in vitro cytotoxicity towards several human tumor cell lines. Particularly, the rhodamine B conjugates 14-16 showed a remarkable cytotoxic activity, characterized by EC values in a low three-digit nanomolar range. The screening of rhodamine B amide 17 that was obtained for comparison by a Schotten-Baumann reaction showed that the linkage of the rhodamine B moiety and the diterpene influences significantly its cytotoxic potency. While 14 was highly cytotoxic and acted as a mitocan, compound 17 was not cytotoxic at all. This observation underlines the importance of the type of coupling between the diterpene and the rhodamine part. The presence of a rhodamine B moiety in the molecules doesn't necessarily guarantee that the compound is cytotoxic.
异氰化物基多组分反应 - 特别是标准的四组分 Ugi 反应 - 为具有良好药理潜力的化合物提供了一种简单而强大的途径。因此，通过 Ugi-4CR 合成了一组 16 种新型松香烷胺的衍生物。随后对合成的 α-酰氨基羧酰胺在比色磺基罗丹明 B 测定中的筛选显示出对几种人类肿瘤细胞系的体外细胞毒性。特别是，罗丹明 B 缀合物 14-16 表现出显著的细胞毒性活性，其 EC 值在低三位数纳摩尔范围内。通过 Schotten-Baumann 反应获得的比较用罗丹明 B 酰胺 17 的筛选表明，罗丹明 B 部分与二萜的连接显著影响其细胞毒性效力。虽然 14 具有高细胞毒性并且作为线粒体毒素起作用，但化合物 17 根本没有细胞毒性。这一观察结果强调了二萜和罗丹明部分之间的连接类型的重要性。分子中存在罗丹明 B 部分不一定保证化合物具有细胞毒性。
