Abstract：
The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure-activity study was carried out, which led to the discovery of several novel compounds (16a-c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5-, 12- and 15-LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA-approved 5-LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α-position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12- and 15-LO products. Compounds 16a, 17a far surpassed baicalein, a known 12-LO inhibitor, as inhibitors of 12-LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α-position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15-LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5-LO active site.
摘要：
脂氧合酶在各种病理中的参与，加上缺乏安全有效的产品生物合成抑制剂，是开发新抑制剂的灵感来源。基于已知的脂氧合酶产物生物合成抑制剂的结构分析，进行了全面的结构活性研究，这导致了几种新化合物的发现(16a-c，17a）证明了抑制5-，12-和15-LO。化合物16b和16c的性能优于齐留通(1)，唯一的FDA批准的5-LO抑制剂，以及已知的抑制剂,例如咖啡酸苯乙酯(CAPE(2))和肉桂基-3,4-二羟基-α-氰基肉桂酸酯(CDC(4))。然而,在羰基的α-位引入氰基消除了活性。化合物16a和17a还抑制12-和15-LO产物的生物合成。化合物16a,17a远远超过了Baicalein，一种已知的12-LO抑制剂，作为12-LO产品生物合成的抑制剂。化合物17a和CDC（4）显示出对LO产物的等效抑制，提出酯部分中的双键对于抑制活性不是必需的。氰基基团的引入，如在化合物17a中，在化合物16a中羰基的α-位显著降低了对15-LO产物生物合成的抑制活性。除了与残基His372和Phe421的相互作用外，zileuton和CAPE也发现，化合物16a和16c各自与残基His367相互作用,如分子对接所示。这种新的相互作用可以解释它们与5-LO活性位点的高亲和力。
