Structure, Absolute Configuration, and Conformational Study of 12-Membered Macrolides from the Fungus Dendrodochium sp. Associated with the Sea Cucumber Holothuria nobilis Selenka

Dendrodolides
A–M (1–13), 13 new 12-membered
macrolides, were isolated from Dendrodochium sp., a fungus associated with the sea
cucumber Holothuria nobilis Selenka,
which was collected from the South China Sea. The structures of the
dendrodolides were elucidated by means of detailed spectroscopic analysis
and X-ray single-crystal diffraction. The absolute configurations
were assigned using the modified Mosher method, exciton-coupled circular
dichroism (ECCD), electronic solution and solid-state circular dichroism
(ECD) supported by time-dependent density functional theory (TDDFT)
ECD calculations, and X-ray analysis. A detailed conformational analysis
of the 13 derivatives indicated that the conformation of the flexible
macrolide ring plays a decisive role in their chiroptical properties.
Thus, it is highly recommended to apply advanced levels of theory
and to avoid simple comparison of ECD spectra to determine the absolute
configurations of these derivatives. In an in vitro bioassay, compounds 1–5, 7–9, 11, and 12 exhibited different levels
of growth inhibitory activity against SMMC-7721 and HCT116 cells.
This is the first report of 12-membered macrolides from the fungus
of the genus Dendrodochium. The coisolation
of four pairs of epimers is extremely interesting and indicates the
complexity of β-ketoreductase stereospecificity in the biosynthesis
of enigmatic iterative fungal polyketides.