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Aspergiolides C and D: Spirocyclic aromatic polyketides with potent protein kinase c-met inhibitory effects

机译:Aspergiolides C和D:具有强力蛋白激酶c-met抑制作用的螺环芳族聚酮化合物

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摘要

Variation of the cultivation conditions for Aspergillus glaucus led to the discovery of two novel spirocyclic aromatic polyketides, aspergiolides C (3) and D (4). Their constitutions were elucidated by a combination of spectroscopic methods and isotope-labeling experiments. Aspergiolides C (3) and D (4) occur as racemic mixtures, the resolution of which was succeeded by HPLC on a chiral phase. The absolute configurations of their enantiomers were assigned online, from the peaks in the chromatogram, by a combination of HPLC-CD and quantum chemical CD calculations. Both compounds were found to inhibit the kinase activities of the receptor tyrosine kinases (RTKs) c-Met, Ron, and c-Src with low-micromolar IC50s. The enantiomers of 3 were resolved by HPLC on a chiral phase. Both enantiomers showed a comparable inhibition of the HGF-induced autophosphorylation of c-Met and of subsequent cell migration.
机译:青曲霉培养条件的变化导致发现了两种新型的螺环芳族聚酮化合物,即曲霉内酯C(3)和D(4)。通过光谱方法和同位素标记实验的结合阐明了它们的组成。曲霉内酯C(3)和D(4)以外消旋混合物形式存在,通过手性相上的HPLC可以成功拆分。通过HPLC-CD和量子化学CD计算的结合,从色谱图中的峰在线分配其对映异构体的绝对构型。发现这两种化合物均具有低微摩尔IC50抑制受体酪氨酸激酶(RTK)c-Met,Ron和c-Src的激酶活性。 3的对映异构体通过HPLC在手性相上拆分。两种对映异构体均显示出对HGF诱导的c-Met自身磷酸化和随后的细胞迁移具有类似的抑制作用。

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