Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii.
Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii.
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DOI：
10.1021/acs.jnatprod.5b00986
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发表时间：
2016-02-26
影响因子：
5.1
通讯作者：
Gunatilaka AA
中科院分区：
文献类型：
--
作者：
Wijeratne EM;Gunaherath GM;Chapla VM;Tillotson J;de la Cruz F;Kang M;U'Ren JM;Araujo AR;Arnold AE;Chapman E;Gunatilaka AA
从 Lecythophora sp. 中分离出一种新的代谢物奥沙螺醇 D (4) 以及奥沙螺醇 B (2) 和 C (3)。 FL1375，一种从 Parmotrematinctorum 中分离出来的内生真菌，而 Lecythophora sp。栖息于地衣 Cladonia evansii 的 FL1031 提供奥沙螺醇 A (1)、B (2) 和 C (3)。其中，奥沙螺醇 B (2) 显示出中等的 p97 ATP 酶抑制活性。对所有奥沙螺醇进行了详细表征，因为为已知奥沙螺醇提出的结构涉及核磁共振波谱数据的不完整分配，仅导致其平面结构。因此，奥沙螺罗 B 的天然异构体混合物（2a 和 2b）被分离为其二乙酸酯（5a 和 5b），并通过应用光谱技术（包括二维 NMR 和改进的 Mosher 酯法）确定了 1、2a、2b、3 和 4 的结构和绝对构型。评估了奥沙螺醇 B (2) 及其二乙酸酯 5a 和 5b 对 p97、p97 突变体和其他 ATP 利用酶的 ATP 酶抑制活性，发现只有 2 种具有活性，表明奥沙螺醇的某些结构特征对其活性有要求。其他生化和细胞测定表明 2 是 p97 的可逆、非 ATP 竞争性和特异性抑制剂。
A new metabolite, oxaspirol D (4), together with oxaspirols B (2) and C (3) were isolated from Lecythophora sp. FL1375, an endolichenic fungus isolated from Parmotrema tinctorum, whereas Lecythophora sp. FL1031 inhabiting the lichen Cladonia evansii afforded oxaspirols A (1), B (2), and C (3). Of these, oxaspirol B (2) showed moderate p97 ATPase inhibitory activity. A detailed characterization of all oxaspirols was undertaken because structures proposed for known oxaspirols have involved incomplete assignments of NMR spectroscopic data leading only to their planar structures. Thus, the naturally occurring isomeric mixture (2a and 2b) of oxaspirol B was separated as their diacetates (5a and 5b) and the structures and absolute configurations of 1, 2a, 2b, 3, and 4 were determined by the application of spectroscopic techniques including two-dimensional NMR and the modified Mosher's ester method. Oxaspirol B (2) and its diacetates 5a and 5b were evaluated for their ATPase inhibitory activities of p97, p97 mutants, and other ATP-utilizing enzymes, and only 2 was found to be active, indicating the requirement of some structural features in oxaspirols for their activity. Additional biochemical and cellular assays suggested that 2 was a reversible, non-ATP competitive, and specific inhibitor of p97.