Structural determinants of blockade of eosinophil activation, adhesion and secretion by synthetic analogs of phomactin.
Structural determinants of blockade of eosinophil activation, adhesion and secretion by synthetic analogs of phomactin.
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DOI：
10.1016/j.lfs.2003.06.001
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发表时间：
2003-10
期刊：
影响因子：
6.1
通讯作者：
Xiangdong Zhu;A. Lambertino;T. Houghton;Jeff D. McGilvra;Chang Xu;V. Rawal;A. Leff
中科院分区：
文献类型：
--
作者：
Xiangdong Zhu;A. Lambertino;T. Houghton;Jeff D. McGilvra;Chang Xu;V. Rawal;A. Leff
我们检查了 phomactin 类似物的结构决定因素，以评估它们作为 PAF 拮抗剂的功效。合成了六种 phomactin 类似物，以确定它们对人嗜酸性粒细胞粘附、超氧化物释放、白三烯 C4(LTC4) 合成和 [3H]PAF 结合的抑制作用。 Phomactin 类似物抑制 PAF 和 IL-5 诱导的嗜酸性粒细胞粘附。类似物A在C-1和C-14之间带有一个烯烃部分，在C-2位置上带有一个酮，以及在C-3和C-4之间带有一个炔部分，具有最大的抗粘连作用。将 C-1 和 C-14 之间的烯烃改为烷烃（类似物 I）使抗粘附作用降低了 2.5-4 倍，而在 C-2 位上用羟基（类似物 G）取代酮则导致抗粘附作用降低了 11 倍。用烯烃（B 和 E）或烷烃（D）取代 C-3 和 C-4 之间的炔部分完全阻断了抗粘附作用。类似物 A 和 I 完全阻断由佛波醇 12-肉豆蔻酸酯 13-乙酸酯或由 fMLP 加细胞松弛素 B 引起的 PAF 和 LTC4 释放引起的嗜酸性粒细胞的超氧化物释放。将 C-3 和 C-4 之间的炔烃部分改为烯烃（B 和 E）或烷烃（D）可完全阻断 phomactin 的这些抑制作用。类似物A降低了[3H]PAF与嗜酸性粒细胞的最大结合，而不改变表观解离常数。我们得出结论，phomactin 类似物是特异性非竞争性 PAF 拮抗剂，在抑制人嗜酸性粒细胞粘附、代谢活性和白三烯分泌方面具有特殊功效。我们进一步定义了 phomactin 分子中调节其抑制功能的结构改变。
We examined the structural determinants of phomactin analogs to assess their efficacy as antagonist of PAF. Six analogs of phomactin were synthesized to determine their inhibitory effects on adhesion, superoxide release, leukotriene C4(LTC4) synthesis and [3H]PAF binding in human eosinophils. Phomactin analogs inhibited both PAF- and IL-5-induced eosinophil adhesion. Analog A, which bears an alkene moiety between C-1 and C-14, a ketone at the C-2 position, and an alkyne moiety between C-3 and C-4, had the greatest anti-adhesive effect. Change of the alkene between C-1 and C-14 to an alkane (analog I) decreased the anti-adhesive effect by 2.5–4 fold, while substitution of ketone by hydroxyl (analog G) at the C-2 position caused an 11-fold decrease in the anti-adhesive effect. Substitution of the alkyne moiety between C-3 and C-4 by an alkene (B and E) or alkane (D) blocked completely the anti-adhesive effect. Analogs A and I completely blocked superoxide release from eosinophils caused by phorbol-12-myristate-13-acetate or PAF and LTC4-release caused by fMLP plus cytochalasin B. Change of the alkyne moiety between C-3 and C-4 to an alkene (B and E) or alkane (D) blocked completely these inhibitory effects of phomactin. Analog A decreased the maximal binding of [3H]PAF binding to eosinophils without change of the apparent dissociation constant. We conclude that phomactin analogs are specific non-competitive PAF antagonists and have exceptional efficacy in inhibiting adhesion, metabolic activity and leukotriene secretion in human eosinophils. We further define the structural alterations in the phomactin molecule that regulate its inhibitory functions.