Jiménez José C, López-Macià Angel, Gracia Carol, Varón Sonia, Carrascal Marta, Caba Josep M, Royo Miriam, Francesch Andrés M, Cuevas Carmen, Giralt Ernest, Albericio Fernando
Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain.
J Med Chem. 2008 Aug 28;51(16):4920-31. doi: 10.1021/jm8000828. Epub 2008 Aug 1.
Kahalalide F (KF) is a natural product currently under phase II clinical trials. Here, we report the solid phase synthesis of 132 novel analogues of kahalalide F and their in vitro activity on a panel of up to 14 cancer cell lines. The structure-activity relationship of these analogues revealed that KF is highly sensitive to backbone stereotopical modification but not to side chain size modification. These observations suggest that this compound has a defined conformational structure and also that it interacts with chiral compounds through its backbone and not through its side chains. The N-terminal aliphatic acid appears to be a hydrophobic buoy in a membrane-like environment. Moreover, significant improvement of the in vitro activity was achieved.
卡哈拉利德F（KF）是一种目前正处于II期临床试验阶段的天然产物。在此，我们报告了132种卡哈拉利德F新型类似物的固相合成及其对多达14种癌细胞系的体外活性。这些类似物的构效关系表明，KF对主链立体异构修饰高度敏感，但对侧链大小修饰不敏感。这些观察结果表明，该化合物具有确定的构象结构，并且它通过主链而非侧链与手性化合物相互作用。N端脂肪酸在类似膜的环境中似乎是一个疏水浮标。此外，体外活性也有显著提高。
