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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.