Derailment of the Biosynthesis via an Acid-Mediated Intramolecular Cyclo-rearrangement Leads to a Novel Cytochalasin Skeleton

Cytochalasins are notable for their structural diversity
and broad
range of biological activities. The gene cluster responsible for the
biosynthesis of cytochalasins bearing diverse polycycles was identified
in Phomopsis sp. DHS-48. Characterization of the
cluster indicated that only the 5/6/11-tricycle can be biosynthetically
produced. The chemical space of cytochalasins was expanded by acid-mediated
intramolecular cyclo-rearrangement of the 5/6/11-tricycle, and three
new cytochalasins, phomoparagins D–F (13, 17, and 18, respectively), with diversified polycycles
were obtained, among which compound 13 featured an unprecedented
5/6/5/7/6-pentacycle. Their structures and absolute configurations
were established by spectroscopic analysis (1D, 2D NMR), electronic
circular dichroism calculations, and a single-crystal X-ray diffraction
experiment. The compounds inhibited the growth of HeLa and RKO cell
lines with IC50 values ranging from 0.8 to 47.3 μM.
Cytoskeleton staining experiments and molecular docking models revealed
that compound 13 showed cytotoxicity by targeting F-actin.