Lee Jean, Chubb Anthony J, Moman Edelmiro, McLoughlin Brian M, Sharkey Caroline T, Kelly John G, Nolan Kevin B, Devocelle Marc, Fitzgerald Desmond J
Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
Org Biomol Chem. 2005 Oct 21;3(20):3678-85. doi: 10.1039/b505525c. Epub 2005 Sep 8.
Currently available non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are directed at the cyclooxygenase (COX) site, but not the peroxidase (POX) activity of prostaglandin H2 synthase (PGHS). They are thus unable to inhibit the free-radical induced tissue injury associated with PGHS peroxidase activity, which can occur independently of the COX site. A lead compound, anthranilic hydroxamic acid (AHA) was found to have significant PGHS-POX inhibitory activity (IC50= 72 microM). To define the critical parameters for PGHS-POX inhibition, we investigated 29 AHA derivatives, synthesised from their acid precursors, using solid phase synthesis. In vitro analysis demonstrated a ten-fold improvement in inhibition with 3,5-diiodoanthranilic hydroxamic acid (IC50= 7 microM).
目前可用的非甾体抗炎药（NSAIDs），如阿司匹林，作用于环氧化酶（COX）位点，但不作用于前列腺素H2合酶（PGHS）的过氧化物酶（POX）活性。因此，它们无法抑制与PGHS过氧化物酶活性相关的自由基诱导的组织损伤，这种损伤可独立于COX位点发生。一种先导化合物邻氨基苯甲酸异羟肟酸（AHA）被发现具有显著的PGHS-POX抑制活性（IC50 = 72 microM）。为了确定PGHS-POX抑制的关键参数，我们使用固相合成法研究了由其酸前体合成的29种AHA衍生物。体外分析表明，3,5-二碘邻氨基苯甲酸异羟肟酸的抑制作用提高了10倍（IC50 = 7 microM）。
