Aspirin-like molecules that covalently inactivate cyclooxygenase-2
Aspirin-like molecules that covalently inactivate cyclooxygenase-2
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DOI：
10.1126/science.280.5367.1268
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发表时间：
1998-05-22
期刊：
影响因子：
56.9
通讯作者：
Marnett, LJ
中科院分区：
文献类型：
--
作者：
Kalgutkar, AS;Crews, BC;Marnett, LJ
阿司匹林的许多治疗作用源于其对环氧合酶-2（考克斯-2）的乙酰化，而其抗血栓形成和致溃疡作用源于其对考克斯-1的乙酰化。在这里，阿司匹林样分子被设计为优先乙酰化和不可逆地抑制考克斯-2。这些化合物中最有效的是o-（乙酰氧基苯基）庚-2-炔基硫醚（APHS）。相对于阿司匹林，APHS对考克斯-2的反应性为60倍，对其抑制的选择性为100倍;它还在培养的巨噬细胞和结肠癌细胞以及大鼠体内气囊中抑制考克斯-2。此类化合物可导致开发用于治疗或预防免疫和增殖性疾病而无胃肠道或血液学副作用的阿司匹林样药物。
Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic effects result from its acetylation of COX-1. Here, aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as reactive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo. Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects.