Institute for Molecular Bioscience, The University of Queensland , St. Lucia, QLD 4072, Australia.
J Org Chem. 2014 Sep 19;79(18):8700-5. doi: 10.1021/jo501501z. Epub 2014 Sep 2.
Chemical analysis of an Australian marine sediment-derived Aspergillus sp. (CMB-M081F) yielded the new diketomorpholine (DKM) shornephine A (1) together with two known and one new diketopiperazine (DKP), 15b-β-hydroxy-5-N-acetyladreemin (2), 5-N-acetyladreemin (3), and 15b-β-methoxy-5-N-acetyladreemin (4), respectively. Structure elucidation of 1-4 was achieved by detailed spectroscopic analysis, supported by chemical degradation and derivatization, and biosynthetic considerations. The DKM (1) underwent a facile (auto) acid-mediated methanolysis to yield seco-shornephine A methyl ester (1a). Our mechanistic explanation of this transformation prompted us to demonstrate that the acid-labile and solvolytically unstable DKM scaffold can be stabilized by N-alkylation. Furthermore, we demonstrate that at 20 μM shornephine A (1) is a noncytotoxic inhibitor of P-glycoprotein-mediated drug efflux in multidrug-resistant human colon cancer cells.
从澳大利亚海洋沉积物来源的曲霉属（CMB-M081F）中进行的化学分析得到了新的二酮吗啉（DKM）shornephine A（1），以及两个已知的和一个新的二酮哌嗪（DKP），15b-β-羟基-5-N-乙酰阿替莫林（2），5-N-乙酰阿替莫林（3）和 15b-β-甲氧基-5-N-乙酰阿替莫林（4）。通过详细的光谱分析，辅以化学降解和衍生化以及生物合成考虑，确定了 1-4 的结构。DKM（1）通过简便的（自动）酸介导的甲醇解反应生成 secoshornephine A 甲酯（1a）。我们对这种转化的机制解释促使我们证明酸不稳定和溶剂不稳定的 DKM 支架可以通过 N-烷基化来稳定。此外，我们证明在 20 μM 时，shornephine A（1）是一种非细胞毒性的 P-糖蛋白介导的多药耐药性人结肠癌细胞中药物外排的抑制剂。
