Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
J Nat Prod. 2014 Jul 25;77(7):1572-8. doi: 10.1021/np4010882. Epub 2014 Jun 25.
The heterocyclic alkaloids, ceratamines A and B, are isolates from a marine Pseudoceratina sp. sponge. They behave as antimitotic agents, with IC50 values in the low micromolar range. The mechanism of this activity involves the disruption of microtubule dynamics; therefore, the ceratamines are of great interest in cancer drug discovery. Studies of in vitro metabolism were performed using rat liver microsomes to begin to understand the pharmacokinetics of these unique natural products. A total of eight metabolites were identified using UV and LC-MS/MS techniques. The majority of metabolites were formed as a result of various demethylation reactions. The formation of two metabolites, M1 and M3, involved monooxygenation, most likely on the aromatic ring, however the exact structure has not been determined. UV absorbance revealed a hypsochromic shift as a result of monooxygenation, an observation that may suggest the loss of aromaticity; however, further investigation is required. The structures of two major metabolites of ceratamine B, M4 and M6, were confirmed by (1)H NMR spectroscopy. These metabolites formed as a result of demethylation at the methoxy and aminoimidazole, respectively.
杂环生物碱角鲨胺 A 和 B 是从海洋拟角鲨属海绵中分离得到的。它们具有抗有丝分裂作用，IC50 值在低微摩尔范围内。这种活性的机制涉及微管动力学的破坏；因此，角鲨胺在癌症药物发现中具有很大的兴趣。使用大鼠肝微粒体进行体外代谢研究，以开始了解这些独特天然产物的药代动力学。使用 UV 和 LC-MS/MS 技术鉴定了总共 8 种代谢物。大多数代谢物是由于各种去甲基化反应形成的。两种代谢物 M1 和 M3 的形成涉及单加氧反应，很可能发生在芳环上，但确切结构尚未确定。由于单加氧作用，UV 吸收发生蓝移，这一观察结果可能表明芳香性的丧失；然而，还需要进一步的研究。角鲨胺 B 的两种主要代谢物 M4 和 M6 的结构通过 1H NMR 光谱得到确认。这些代谢物是由于甲氧基和氨基咪唑的去甲基化形成的。
