Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, UFR des Sciences Exactes et Naturelles, 51687 Reims Cedex 2, France.
Chemistry. 2013 Jul 15;19(29):9526-33. doi: 10.1002/chem.201301001. Epub 2013 Jun 5.
Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking (3)E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100% inhibition of the proliferation of MDA-MB-231 cancer cells at 50 μM.
通过过度表达岩藻糖苷酶增强岩藻糖代谢是一些癌症类型的特征，因此表明岩藻糖苷酶靶向配体可以发挥药物输送载体的作用。在此，我们描述了一系列新的吡咯烷-二茂铁缀合物的合成，该缀合物由 L-岩藻糖构型的二羟吡咯烷作为岩藻糖苷酶配体，带有细胞毒性的二茂铁胺部分。这些岩藻糖苷酶抑制剂的三维结构揭示了过渡态模拟（3）E 构象。用茂铁部分进行修饰导致牛和细菌岩藻糖苷酶的亚微摩尔抑制剂，后者的三维结构显示出电子密度表明高度可移动的烷基茂铁化合物。最好的化合物表现出强烈的抗增殖作用，在 50μM 时对 MDA-MB-231 癌细胞的增殖抑制率高达 100%。
