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Ugi multicomponent-reaction: Syntheses of cytotoxic dehydroabietylamine derivatives
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2018-09-11 , DOI: 10.1016/j.bioorg.2018.09.014
Jana Wiemann , Lucie Fischer (née Heller) , Jacqueline Kessler , Dieter Ströhl , René Csuk

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 1416 showed a remarkable cytotoxic activity, characterized by EC50 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.



中文翻译:

Ugi多组分反应:细胞毒性脱氢松香胺衍生物的合成

基于异氰化物的多组分反应-尤其是标准的四组分Ugi反应-提供了具有强大药理潜力的化合物的简便而有效的获取途径。因此,通过Ugi-4CR合成了一组16种二萜脱氢松香胺的新型衍生物。在比色磺基若丹明B分析中对合成的α-酰基氨基羧酰胺的后续筛选显示了对几种人类肿瘤细胞系的体外细胞毒性。具体地,若丹明B色缀合物14 - 16显示显着的细胞毒活性,其特征在于通过EC 50倍在低三位数纳摩尔范围内的值。罗丹明B酰胺的筛选17通过Schotten-Baumann反应获得的用于比较的结果表明,若丹明B部分与二萜的连接显着影响其细胞毒性。虽然14具有高度的细胞毒性并可以充当线粒体,但化合物17完全没有细胞毒性。该观察结果强调了二萜与若丹明部分之间偶联类型的重要性。分子中若丹明B部分的存在并不一定保证该化合物具有细胞毒性。

更新日期:2018-09-11
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