Vintonyak Viktor V, Calà Marcellino, Lay Frank, Kunze Brigitte, Sasse Florenz, Maier Martin E
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.
Chemistry. 2008;14(12):3709-20. doi: 10.1002/chem.200701673.
The complex macrolide cruentaren A is a highly selective and potent inhibitor of F-ATPase (F-type adenosine triphosphatase). As it shows some resemblance to benzolactone enamides like apicularen A, it was of interest to perform some structure-activity studies to delineate the key functional groups that are responsible for the activity. Building upon our previously developed route to cruentaren A, which is based on a ring-closing alkyne metathesis reaction (RCAM), several cruentaren analogues were prepared. Replacement of the 3-hydroxy hexanoic part with acids that lack the hydroxy group function resulted in a significant drop in cytotoxicity and F-ATPase inhibition. Furthermore, two enamide analogues 23 and 50 were synthesized. However, these compounds were only cytotoxic in the micromolar range. Under the conditions for cleavage of the C3 aromatic methyl ether, the enamide function was transformed to the corresponding oxazinanone, resulting in analogues 25 and 52.
复杂的大环内酯克鲁恩他仁A是F-ATP酶（F型腺苷三磷酸酶）的一种高度选择性和强效抑制剂。由于它与诸如阿皮拉仁A之类的苯并内酯烯酰胺有一些相似之处，因此进行一些构效关系研究以确定负责该活性的关键官能团是很有意义的。基于我们先前开发的以闭环炔烃复分解反应（RCAM）为基础的合成克鲁恩他仁A的路线，制备了几种克鲁恩他仁类似物。用缺乏羟基官能团的酸取代3-羟基己酸部分导致细胞毒性和F-ATP酶抑制作用显著下降。此外，合成了两种烯酰胺类似物23和50。然而，这些化合物仅在微摩尔范围内具有细胞毒性。在C3芳族甲基醚裂解的条件下，烯酰胺官能团转化为相应的恶嗪烷酮，得到类似物25和52。
