Exploring sponge-derived terpenoids for their potency and selectivity against 12-human, 15-human, and 15-soybean lipoxygenases
Exploring sponge-derived terpenoids for their potency and selectivity against 12-human, 15-human, and 15-soybean lipoxygenases
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DOI：
10.1021/np020462l
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发表时间：
2003-02-01
影响因子：
5.1
通讯作者：
Holman, TR
中科院分区：
文献类型：
--
作者：
Amagata, T;Whitman, S;Holman, TR
为了加强寻找新的脂氧合酶抑制剂，我们设计了一个屏幕，以探测的效力和选择性。该试验使用12-人（12-HLO）、15-人（15-HLO）和15-大豆（15-SLO）脂肪氧合酶。获得的IC 50值数据为氧化还原和非氧化还原抑制剂的结构-活性关系（SAR）提供了新的见解。所有测试的化合物都是从海绵中分离出来的，包括一种新的萜类化合物，hyrtenone A（1）和12种已知的萜类化合物。有效化合物定义为IC 50值< 1 μ M的化合物，并从三种可能的IC 50值比率评估选择性。研究的四种萜类氧化还原抑制剂之一，puupehenone（2），在效力上相当于或优于众所周知的氧化还原抑制剂去甲二氢guarierate酸（NDGA，14）。然而，没有一个萜烯氧化还原抑制剂表现出与14的选择性比相当。几种有效的非氧化还原抑制剂被鉴定出来，其中一种，二甲氧基普乌苯酚（5），表现出显著的选择性。报道了化合物1的结构鉴定和13种天然产物的构效关系。这项研究表明，海绵衍生的萜烯是一个有前途的来源，新的脂氧合酶抑制剂。
To sharpen the search for new lipoxygenase inhibitors, we designed a screen to probe for both potency and selectivity. The assay utilized 12-human (12-HLO), 15-human (15-HLO), and 15-soybean (15-SLO) lipoxygenases. The IC50 value data obtained provided new insights about structure-activity relationships (SAR) for redox and nonredox inhibitors. All of the compounds tested were isolated from sponges and consisted of a novel terpenoid, hyrtenone A (1), and 12 known terpenoids. Potent compounds were defined as those having IC50 values < 1 muM, and selectivity was assessed from the three possible IC50 value ratios. One of the four terpenoid redox inhibitors studied, puupehenone (2), was equivalent to or better in potency than the well-known redox inhibitor nordihydroguarierate acid (NDGA, 14). However, none of the terpene redox inhibitors exhibited a selectivity ratio on a par with that of 14. Several potent nonredox inhibitors were identified, and one, dimethoxypuupehenol (5), exhibited notable selectivity. The structural elucidation of 1 and the SAR results for 13 natural products are reported. This study suggests that sponge-derived terpenes are a promising source for new lipoxygenase inhibitors.