Higginsianins A and B, Two Diterpenoid α‑Pyrones Produced by <i>Colletotrichum higginsianum</i>, with <i>in Vitro</i> Cytostatic Activity

Abstract

Two new diterpenoid α-pyrones, named higginsianins A (<b>1</b>) and B (<b>2</b>), were isolated from the mycelium of the fungus <i>Colletotrichum higginsianum</i> grown in liquid culture. They were characterized as 3-[5a,9b-dimethyl-7-methylene-2-(2-methylpropenyl)­dodecahydro­naphtho­[2,1-<i>b</i>]­furan-6-ylmethyl]-4-hydroxy-5,6-dimethylpyran-2-one and 4-hydroxy-3-[6-hydroxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)­decahydro­naphthalen-1-ylmethyl]-5,6-dimethylpyran-2-one, respectively, by using NMR, HRESIMS, and chemical methods. The structure and relative configuration of higginsianin A (<b>1</b>) were confirmed by X-ray diffractometric analysis, while its absolute configuration was assigned by electronic circular dichroism (ECD) experiments and calculations using a solid-state ECD/TDDFT method. The relative and absolute configuration of higginsianin B (<b>2</b>), which did not afford crystals suitable for X-ray analysis, were determined by NMR analysis and by ECD in comparison with higginsianin A. <b>1</b> and <b>2</b> were the C-8 epimers of subglutinol A and diterpenoid BR-050, respectively. The evaluation of <b>1</b> and <b>2</b> for antiproliferative activity against a panel of six cancer cell lines revealed that the IC₅₀ values, obtained with cells reported to be sensitive to pro-apoptotic stimuli, are by more than 1 order of magnitude lower than their apoptosis-resistant counterparts (1 vs >80 μM). Finally, three hemisynthetic derivatives of <b>1</b> were prepared and evaluated for antiproliferative activity. Two of these possessed IC₅₀ values and differential sensitivity profiles similar to those of <b>1</b>