基于咖啡酸苯乙酯的抑制剂的设计、合成与评价：针对人醛酮还原酶 1B10 活性部位的一个选择性口袋。

Design, synthesis and evaluation of caffeic acid phenethyl ester-based inhibitors targeting a selectivity pocket in the active site of human aldo-keto reductase 1B10.

机构信息

Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.

出版信息

Eur J Med Chem. 2012 Feb;48:321-9. doi: 10.1016/j.ejmech.2011.12.034. Epub 2011 Dec 29.

DOI:10.1016/j.ejmech.2011.12.034

Abstract

Inhibitors of a human aldo-keto reductase, AKR1B10, are regarded as promising therapeutics for the treatment of cancer, but those with both high potency and selectivity compared to the structurally similar aldose reductase (AKR1B1) have not been reported. In this study, we have found that, among honeybee propolis products, caffeic acid phenethyl ester (CAPE) inhibited AKR1B10 (IC(50) = 80 nM) with 7-fold selectivity over AKR1B1. Based on a model of docked CAPE in AKR1B10, its derivatives were designed, synthesized and evaluated for inhibitory potency. Among them, 3-(4-hydroxy-2-methoxyphenyl)acrylic acid 3-(3-hydroxyphenyl)propyl ester (10c) was the most potent competitive inhibitor (K(i) = 2.6 nM) with 790-fold selectivity for AKR1B10 over AKR1B1. Molecular docking of 10c and site-directed mutagenesis of AKR1B10 residues suggested that the interactions between the 2-methoxy and 3-hydroxy groups of 10c and the enzyme's Val301 and Gln114, respectively, are important for the inhibitor's selectivity. Additionally, the sub-μM concentration of 10c significantly suppressed the farnesal metabolism and cellular proliferation in AKR1B10-overexpressing cells.

摘要

人类醛酮还原酶 1B10（AKR1B10）的抑制剂被认为是治疗癌症的有前途的治疗药物，但与结构相似的醛糖还原酶（AKR1B1）相比，具有高活性和选择性的抑制剂尚未报道。在这项研究中，我们发现，在蜜蜂蜂胶产品中，咖啡酸苯乙酯（CAPE）对 AKR1B10 的抑制作用（IC50=80nM）具有 7 倍的选择性，优于 AKR1B1。基于 CAPE 在 AKR1B10 中的对接模型，设计、合成并评估了其衍生物的抑制活性。其中，3-（4-羟基-2-甲氧基苯基）丙烯酸 3-（3-羟基苯基）丙酯（10c）是最有效的竞争性抑制剂（K i=2.6nM），对 AKR1B10 的选择性为 AKR1B1 的 790 倍。10c 的分子对接和 AKR1B10 残基的定点突变表明，10c 的 2-甲氧基和 3-羟基与酶的 Val301 和 Gln114 之间的相互作用对于抑制剂的选择性很重要。此外，亚微摩尔浓度的 10c 可显著抑制 AKR1B10 过表达细胞中的法呢醛代谢和细胞增殖。