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

Abstract

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, <b>1</b>-<b>71</b>) and eight known (<b>72</b>-<b>79</b>) aphidicolin congeners from <i>Botryotinia fuckeliana</i> MCCC 3A00494, a fungus isolated from the western Pacific Ocean (-5572 m). The structures of <b>1</b>-<b>71</b> were determined through extensive spectroscopic analysis, X-ray crystallography, chemical derivatization, modified Mosher's method, and the ECD exciton chirality method. Compounds <b>54</b>-<b>57</b> and <b>58</b>-<b>64</b> are novel 6/6/5/6/5 pentacyclic aphidicolins featuring tetrahydrofuran and dihydrofuran rings, respectively, while compounds <b>65</b>-<b>71</b> are rare noraphidicolins. Aphidicolin A8 (<b>8</b>) 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, <b>8</b> was found to form tight intermolecular contacts, elaborating aphidicolin A8 as a potently cytotoxic lead compound.