Diazonamide A and a synthetic structural analog: Disruptive effects on mitosis and cellular microtubules and analysis of their interactions with tubulin
Diazonamide A and a synthetic structural analog: Disruptive effects on mitosis and cellular microtubules and analysis of their interactions with tubulin
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DOI：
10.1124/mol.63.6.1273
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发表时间：
2003-06-01
影响因子：
3.6
通讯作者：
Hamel, E
中科院分区：
文献类型：
--
作者：
Cruz-Monserrate, Z;Vervoort, HC;Hamel, E
海洋海鞘Diazona angulata是复合细胞毒肽重氮酰胺A的来源生物。该肽的分子结构最近在重氮酰胺A的生物活性类似物合成后进行了修订，其中单个氮原子被氧原子取代。重氮酰胺A导致细胞在有丝分裂中停滞，并且在暴露于药物后，处理的细胞失去间期和纺锤体微管。重氮酰胺A和氧类似物都是微管组装的有效抑制剂，活性与多拉司他汀10相当，因此比多拉司他汀15有效得多。微管组装的这种抑制伴随着微管蛋白依赖性GTP水解的有效抑制，也与用多拉司他汀10观察到的效果相当。然而，重氮酰胺A及其类似物的其余生物化学性质与海兔毒素10的性质显著不同，并且与海兔毒素15的性质非常相似。重氮酰胺A和类似物均不抑制[H-3]长春碱、[H-3]多拉司他汀10或[8-C-14] GTP与微管蛋白的结合。它们也不能稳定微管蛋白的秋水仙素结合活性。这些观察结果表明，无论是重氮酰胺A和类似物具有独特的结合位点微管蛋白上的长春花生物碱和海兔毒素10结合位点不同，或重氮酰胺A和类似物结合弱未聚合的微管蛋白，但强烈的微管末端。如果后者是正确的，diazonamide A和它的氧类似物应该有独特的有效抑制作用的微管的动态特性。
The marine ascidian Diazona angulata was the source organism for the complex cytotoxic peptide diazonamide A. The molecular structure of this peptide was recently revised after synthesis of a biologically active analog of diazonamide A in which a single nitrogen atom was replaced by an oxygen atom. Diazonamide A causes cells to arrest in mitosis, and, after exposure to the drug, treated cells lose both interphase and spindle microtubules. Both diazonamide A and the oxygen analog are potent inhibitors of microtubule assembly, equivalent in activity to dolastatin 10 and therefore far more potent than dolastatin 15. This inhibition of microtubule assembly is accompanied by potent inhibition of tubulin-dependent GTP hydrolysis, also comparable with the effects observed with dolastatin 10. However, the remaining biochemical properties of diazonamide A and its analog differ markedly from those of dolastatin 10 and closely resemble the properties of dolastatin 15. Neither diazonamide A nor the analog inhibited the binding of [H-3] vinblastine, [H-3] dolastatin 10, or [8-C-14] GTP to tubulin. Nor were they able to stabilize the colchicine binding activity of tubulin. These observations indicate either that diazonamide A and the analog have a unique binding site on tubulin differing from the vinca alkaloid and dolastatin 10 binding sites, or that diazonamide A and the analog bind weakly to unpolymerized tubulin but strongly to microtubule ends. If the latter is correct, diazonamide A and its oxygen analog should have uniquely potent inhibitory effects on the dynamic properties of microtubules.