Aphidicolin Chemistry of the Deep-Sea-Derived Fungus <i>Botryotinia fuckeliana</i> MCCC 3A00494

Aphidicolin, a potent DNA polymerase α inhibitor, has been explored in clinical trials for the treatment of cancer. So far, about 300 modified aphidicolins have been discovered. However, none have shown a stronger effect. Herein, we report 71 new (aphidicolins A1–A71, 1–71) and eight known (72–79) aphidicolin congeners from Botryotinia fuckeliana MCCC 3A00494, a fungus isolated from the western Pacific Ocean (−5572 m). The structures of 1–71 were determined through extensive spectroscopic analysis, X-ray crystallography, chemical derivatization, modified Mosher’s method, and the ECD exciton chirality method. Compounds 54–57 and 58–64 are novel 6/6/5/6/5 pentacyclic aphidicolins featuring tetrahydrofuran and dihydrofuran rings, respectively, while compounds 65–71 are rare noraphidicolins. Aphidicolin A8 (8) significantly induced apoptosis in T24 (IC50 = 2.5 μM) and HL-60 (IC50 = 6.1 μM) cancer cells by causing DNA damage. By docking its structure to the human DNA polymerase α binding pocket, 8 was found to form tight intermolecular contacts, elaborating aphidicolin A8 as a potently cytotoxic lead compound.阿非迪霉素（Aphidicolin）是一种强效的DNA聚合酶α（DNA polymerase α）抑制剂，已被用于癌症治疗的临床试验。截至目前，已发现约300种修饰型阿非迪霉素，但尚未有活性更强的同类化合物被报道。本研究从西太平洋（-5572米）海域分离得到的真菌富氏葡萄孢盘菌（Botryotinia fuckeliana）MCCC 3A00494中，分离得到71个全新的阿非迪霉素类同源物（aphidicolins A1–A71，1–71）以及8个已知同源物（72–79）。通过全面的波谱分析、X射线晶体衍射（X-ray crystallography）、化学衍生法、改进型Mosher法（modified Mosher’s method）以及电子圆二色性（ECD）激子手性法，确定了化合物1–71的化学结构。其中，化合物54–57与58–64分别为带有四氢呋喃环和二氢呋喃环的新型6/6/5/6/5五环型阿非迪霉素类化合物，而化合物65–71则为罕见的去甲阿非迪霉素类（noraphidicolins）衍生物。阿非迪霉素A8（8）可通过诱导DNA损伤，显著促进T24细胞（半最大效应浓度（IC50）= 2.5 μM）与HL-60细胞（IC50 = 6.1 μM）发生细胞凋亡。将其结构与人DNA聚合酶α结合口袋进行分子对接后发现，化合物8可与该口袋形成紧密的分子间相互作用，证实阿非迪霉素A8是一种强效的细胞毒性先导化合物。