2-(氨基烷基)吡咯烷-3,4-二醇衍生物的合成及其糖苷酶抑制活性

Synthesis and glycosidase inhibitory activities of 2-(aminoalkyl)pyrrolidine-3,4-diol derivatives.

作者信息

Carmona Ana T, Popowycz Florence, Gerber-Lemaire Sandrine, Rodríguez-García Eliazar, Schütz Catherine, Vogel Pierre, Robina Inmaculada

机构信息

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, E-41071, Seville, Spain.

出版信息

Bioorg Med Chem. 2003 Nov 17;11(23):4897-911. doi: 10.1016/j.bmc.2003.09.020.

DOI:10.1016/j.bmc.2003.09.020

PMID:14604651

Abstract

Several 2-(aminomethyl)-and 2-(2-aminoethyl)-pyrrolidine-3,4-diol derivatives have been assayed for their inhibitory activities towards glycosidases. Good inhibitors of alpha-mannosidases must have the (2R,3R,4S) configuration and possess 2-(benzylamino)methyl substituents. Stereomers with the (2S,3R,4S) configuration are also competitive inhibitors of alpha-mannosidases, but less potent as they share the configuration of C(1), C(2), C(3) of beta-D-mannosides rather than that of alpha-D-mannosides. Interestingly, (2S,3R,4S)-2-[2-[(4-phenyl)phenylamino]ethyl]pyrrolidine-3,4-diol (12g) inhibits several enzymes, for instance alpha-L-fucosidase from bovine epididymis (K(i)=6.5microM, competitive), alpha-galactosidase from bovine liver (K(i)=5microM, mixed) and alpha-mannosidase from jack bean (K(i)=102microM, mixed). Diamines such as (2R,3S,4R)-2-[2-(phenylamino) or 2-(benzylamino)ethyl]pyrrolidine-3,4-diol (ent-12a, ent-12b) inhibit beta-glucosidase from almonds (K(i)=13-40microM, competitive).

摘要

已对几种2-(氨甲基)-和2-(2-氨基乙基)-吡咯烷-3,4-二醇衍生物进行了糖苷酶抑制活性测定。α-甘露糖苷酶的良好抑制剂必须具有(2R,3R,4S)构型并带有2-(苄基氨基)甲基取代基。具有(2S,3R,4S)构型的立体异构体也是α-甘露糖苷酶的竞争性抑制剂，但效力较低，因为它们具有β-D-甘露糖苷的C(1)、C(2)、C(3)构型，而不是α-D-甘露糖苷的构型。有趣的是，(2S,3R,4S)-2-[2-[(4-苯基)苯基氨基]乙基]吡咯烷-3,4-二醇(12g)抑制多种酶，例如来自牛附睾的α-L-岩藻糖苷酶(Ki = 6.5μM，竞争性)、来自牛肝的α-半乳糖苷酶(Ki = 5μM，混合型)和来自刀豆的α-甘露糖苷酶(Ki = 102μM，混合型)。二胺如(2R,3S,4R)-2-[2-(苯基氨基)或-2-(苄基氨基)乙基]吡咯烷-3,4-二醇(对映体-12a，对映体-12b)抑制来自杏仁的β-葡萄糖苷酶(Ki = 13 - 40μM，竞争性)。