Van den Worm E, Beukelman C J, Van den Berg A J, Kroes B H, Labadie R P, Van Dijk H
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Faculty of Pharmacy, Utrecht University, PO Box 80082, 3508 TB, Utrecht, The Netherlands.
Eur J Pharmacol. 2001 Dec 21;433(2-3):225-30. doi: 10.1016/s0014-2999(01)01516-3.
Owing to their multiple side effects, the use of steroidal drugs is becoming more and more controversial, resulting in an increasing need for new and safer anti-inflammatory agents. In the inflammatory process, reactive oxygen species produced by phagocytic cells are considered to play an important role. We showed that apocynin (4'-hydroxy-3'-methoxy-acetophenone or acetovanillone), a non-toxic compound isolated from the medicinal plant Picrorhiza kurroa, selectively inhibits reactive oxygen species production by activated human neutrophils. Apocynin proved to be effective in the experimental treatment of several inflammatory diseases such as arthritis, colitis and atherosclerosis. These features suggest that apocynin could be a prototype of a novel series of non-steroidal anti-inflammatory drugs (NSAIDs). So far, apocynin is mainly used in vitro to block NADPH oxidase-dependent reactive oxygen species generation by neutrophils. In order to get a better insight in what chemical features play a role in the anti-inflammatory effects of apocynin, a structure-activity relationship study with apocynin analogs was performed. We show here that especially substances with an additional methoxy group at position C-5 display enhanced anti-inflammatory activity in vitro. Our approach may lead to the development of more effective anti-inflammatory agents which are safe and which lack the side effects of steroids.
由于甾体类药物存在多种副作用，其使用正变得越来越具有争议性，这使得对新型且更安全的抗炎药的需求日益增加。在炎症过程中，吞噬细胞产生的活性氧被认为起着重要作用。我们发现，从药用植物胡黄连中分离出的一种无毒化合物阿朴色原酮（4'-羟基-3'-甲氧基苯乙酮或乙酰香草酮）能够选择性抑制活化的人类中性粒细胞产生活性氧。阿朴色原酮在关节炎、结肠炎和动脉粥样硬化等多种炎症性疾病的实验治疗中被证明是有效的。这些特性表明阿朴色原酮可能是一系列新型非甾体抗炎药（NSAIDs）的原型。到目前为止，阿朴色原酮主要用于体外实验，以阻断中性粒细胞中依赖烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生活性氧的过程。为了更深入了解哪些化学特征在阿朴色原酮的抗炎作用中发挥作用，我们对阿朴色原酮类似物进行了构效关系研究。我们在此表明，尤其是在C-5位带有额外甲氧基的物质在体外显示出增强的抗炎活性。我们的方法可能会促使开发出更有效的抗炎药物，这些药物安全且没有甾体类药物的副作用。
