Cruz Luis J, Francesch Andres, Cuevas Carmen, Albericio Fernando
Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona, 08028-Barcelona, Spain.
ChemMedChem. 2007 Jul;2(7):1076-84. doi: 10.1002/cmdc.200700025.
Several recently discovered marine products have remarkable in vitro and in vivo anticancer profiles against a wide range of tumor cell lines. Some of these compounds are currently in clinical trials. These compounds show complex structures and mechanisms of action of interest. Herein, we describe the preparation of a series of totally synthetic molecules that are structurally related to the natural marine product IB-01212 and evaluated them as antitumor agents. For this, total solid-phase syntheses of the products were performed in parallel by two distinct routes: linear synthesis and convergent synthesis. Structural modifications were introduced in several residue positions to afford 21 IB-01212 analogues for structure-relationship studies. An increase in the number of methyl groups in the macrocycle enhanced cytotoxic activity. Also, the replacement of an ester bond by an amide bond favored antitumor activity against several human cell lines. In addition, the L configuration analogues were more active against all the tumor cell lines than those containing the D configuration. A significant increase in the size and asymmetry of the macrocycle diminished biological activity with respect to that of IB-01212. These results are of great value for the discovery of new and more effective anticancer agents.
最近发现的几种海洋产物对多种肿瘤细胞系具有显著的体外和体内抗癌活性。其中一些化合物目前正在进行临床试验。这些化合物具有复杂的结构和作用机制。在此，我们描述了一系列与天然海洋产物IB - 01212结构相关的全合成分子的制备，并将它们作为抗肿瘤剂进行评估。为此，通过两种不同的路线平行进行产物的全固相合成：线性合成和汇聚合成。在几个残基位置引入结构修饰，以提供21种IB - 01212类似物用于构效关系研究。大环中甲基数量的增加增强了细胞毒性活性。此外，用酰胺键取代酯键有利于对几种人类细胞系的抗肿瘤活性。另外，L构型类似物对所有肿瘤细胞系的活性均高于含有D构型的类似物。相对于IB - 01212，大环尺寸和不对称性的显著增加降低了生物活性。这些结果对于发现新的、更有效的抗癌药物具有重要价值。
