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Lienhwalides: Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense
Author(s) -
Schmidt Katharina,
CharriaGirón Esteban,
Gorelik Tatiana E.,
Kleeberg Christian,
Muema Jackson M.,
Heitkämper Simone,
Verwaaijen Bart,
Kuhnert Eric,
Gerke Jennifer,
Kalinowski Jörn,
Hyde Kevin D.,
Stadler Marc,
Cox Russell,
Surup Frank
Publication year - 2025
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202500037
Subject(s) - tropolone , biogenesis , chemistry , stereochemistry , biosynthesis , derivative (finance) , metabolite , carbon 13 nmr , heterologous expression , nuclear magnetic resonance spectroscopy , biochemistry , organic chemistry , gene , financial economics , economics , recombinant dna
Hypoxylon lienhwacheense , a fungal species with an unclear taxonomic placement within the Hypoxylaceae, presents a highly rare stromatal secondary metabolite profile. Isolation of its major stromatal constituents leads to the discovery of a novel tropolone–maleidride hybrid molecule, lienhwalide A 5 , in addition to the known cordyanhydride B 6 , its new derivative 7 , and binaphthalenetetraol 8 . Unexpectedly, Hypoxylon lienhwacheense produces in liquid cultures various lienhwalide A congeners 9 – 11 . Their structures and relative configurations are elucidated using high‐resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, with their absolute configurations determined using X‐ray analysis of a semisynthetic brominated derivative of 9 and synthesizing α‐methoxy‐α‐trifluoromethylphenylacetyl esters of 11 . Feeding experiments with 13 C‐labeled precursors ( 13 C‐methionine; 1‐ 13 C‐ and U‐ 13 C 6 ‐glucose) reveal insights into the biogenesis of tropolone and maleidride moieties, according to 13 C couplings and incredible natural abundance double quantum transfer NMR data. Genome analysis identifies two separate biosynthetic gene clusters responsible for these moieties, and heterologous expression experiments provide further insights into the interplay of both clusters during the biosynthesis of these hybrid natural products. Remarkably, lienhwalides exhibit reduced toxicity and enhance antibacterial selectivity compared to related fungal tropolones.