非氧化型非竞争性白三烯生物合成抑制剂乙酰-11-酮-β-乳香酸的构效关系。

Structure-activity relationships of the nonredox-type non-competitive leukotriene biosynthesis inhibitor acetyl-11-keto-β-boswellic acid.

机构信息

Department of Pharmacology, Institute for Pharmaceutical Sciences, University of Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingten, Germany.

出版信息

Phytomedicine. 1996 May;3(1):73-4. doi: 10.1016/S0944-7113(96)80014-6.

DOI:10.1016/S0944-7113(96)80014-6

PMID:23194865

Abstract

Acetyl-11-keto-β-boswellic acid (AKBA) from Boswellia serrata Roxb. and italics Boswellia carterii Birdw. is the first selective, direct, non-competitive and non-redox-type inhibitor of 5-lipoxygenase, the key enzyme for leukotriene biosynthesis (Safayhi et al., 1992). Previously, we showed that AKBA interacts with the 5-lipoxygenase via a pentacyclic triterpene selective effector site (Safayhi et al., 1995). In order to study the impact of AKBA's functional groups on enzyme inhibition, natural and synthetic analogues of this boswellic acid were tested for 5-lipoxygenase inhibition in intact rat neutrophils (Sailer et al., 1996 a). The results reveal that the carboxylic group of AKBA combined with the 11-keto-group is essential for enzyme inhibition, whereas the acetoxy-group on position C-3 α increases the affinity of AKBA to its effector site. Furthermore, other experiments demonstrated that minor structural modifications could cause a total loss of binding affinity and/or inhibitory activity of these compounds.

摘要

乙酰-11-酮-β-乳香酸（AKBA）来源于 Boswellia serrata Roxb. 和 Boswellia carterii Birdw.，是 5-脂氧合酶（leukotriene biosynthesis 的关键酶）的第一个选择性、直接、非竞争性和非氧化还原型抑制剂（Safayhi 等人，1992 年）。此前，我们已经证明 AKBA 通过五环三萜选择性效应部位与 5-脂氧合酶相互作用（Safayhi 等人，1995 年）。为了研究 AKBA 的官能团对酶抑制的影响，对这种乳香酸的天然和合成类似物进行了完整的大鼠嗜中性粒细胞 5-脂氧合酶抑制试验（Sailer 等人，1996 年 a）。结果表明，AKBA 的羧酸基团与 11-酮基团结合对于酶抑制是必不可少的，而 C-3α位上的乙酰氧基基团增加了 AKBA 与其效应部位的亲和力。此外，其他实验表明，微小的结构修饰可能导致这些化合物的结合亲和力和/或抑制活性完全丧失。