Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, FL, 32610, USA.
Department of Plant Pathology, University of Florida, Gainesville, 32611, FL, USA.
Chembiochem. 2021 Jan 15;22(2):416-422. doi: 10.1002/cbic.202000403. Epub 2020 Sep 30.
Some fungal epithiodiketopiperazine alkaloids display α,β-polysulfide bridges alongside diverse structural variations. However, the logic of their chemical diversity has rarely been explored. Here, we report the identification of three new (2, 3, 8) and five known (1, 4-7) epithiodiketopiperazines of this subtype from a marine-derived Penicillium sp. The structure elucidation was supported by multiple spectroscopic analyses. Importantly, we observed multiple nonenzymatic interconversions of these analogues in aqueous solutions and organic solvents. Furthermore, the same biosynthetic origin of these compounds was supported by one mined gene cluster. The dominant analogue (1) demonstrated selective cytotoxicity to androgen-sensitive prostate cancer cells and HIF-depleted colorectal cells and mild antiaging activities, linking the bioactivity to oxidative stress. These results provide crucial insight into the formation of fungal epithiodiketopiperazines through chemical interconversions.
一些真菌的表硫二酮哌嗪生物碱除了具有多样化的结构变化外，还显示出α，β-多硫化物桥。然而，其化学多样性的逻辑很少被探索。在这里，我们报道了从海洋来源的青霉属中鉴定出的三种新型（2,3,8）和五种已知（1,4-7）表硫二酮哌嗪生物碱。结构阐明得到了多种光谱分析的支持。重要的是，我们观察到这些类似物在水溶液和有机溶剂中的多种非酶相互转化。此外，通过一个挖掘的基因簇支持了这些化合物的相同生物合成来源。主要类似物（1）对雄激素敏感的前列腺癌细胞和 HIF 耗尽的结肠癌细胞表现出选择性细胞毒性，并具有轻度的抗衰老活性，将生物活性与氧化应激联系起来。这些结果为通过化学互变形成真菌的表硫二酮哌嗪提供了重要的见解。
