Main content area

Higginsianins A and B, Two Diterpenoid α-Pyrones Produced by Colletotrichum higginsianum, with in Vitro Cytostatic Activity

Cimmino, Alessio, Mathieu, Veronique, Masi, Marco, Baroncelli, Riccardo, Boari, Angela, Pescitelli, Gennaro, Ferderin, Marlène, Lisy, Romana, Evidente, Marco, Tuzi, Angela, Zonno, Maria Chiara, Kornienko, Alexander, Kiss, Robert, Evidente, Antonio
Journal of natural products 2016 v.79 no.1 pp. 116-125
Colletotrichum higginsianum, X-radiation, X-ray diffraction, apoptosis, circular dichroism spectroscopy, crystals, diterpenoids, fungi, inhibitory concentration 50, mycelium, neoplasms, nuclear magnetic resonance spectroscopy
Two new diterpenoid α-pyrones, named higginsianins A (1) and B (2), were isolated from the mycelium of the fungus Colletotrichum higginsianum grown in liquid culture. They were characterized as 3-[5a,9b-dimethyl-7-methylene-2-(2-methylpropenyl)dodecahydronaphtho[2,1-b]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 (1) 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 (2), which did not afford crystals suitable for X-ray analysis, were determined by NMR analysis and by ECD in comparison with higginsianin A. 1 and 2 were the C-8 epimers of subglutinol A and diterpenoid BR-050, respectively. The evaluation of 1 and 2 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 1 were prepared and evaluated for antiproliferative activity. Two of these possessed IC₅₀ values and differential sensitivity profiles similar to those of 1.