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

By Alessio Cimmino, Veronique Mathieu, Marco Masi, Riccardo Baroncelli, Angela Boari, Gennaro Pescitelli, Marlène Ferderin, Romana Lisy, Marco Evidente, Angela Tuzi, Maria Chiara Zonno, Alexander Kornienko, Robert Kiss, Antonio Evidente

July 28, 2017

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Title

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

Author

Alessio Cimmino, Veronique Mathieu, Marco Masi, Riccardo Baroncelli, Angela Boari, Gennaro Pescitelli, Marlène Ferderin, Romana Lisy, Marco Evidente, Angela Tuzi, Maria Chiara Zonno, Alexander Kornienko, Robert Kiss, Antonio Evidente

Year

2016

Journal

Journal of Natural Products

Abstract

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.

Full Article

http://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.5b00779

Instrument

J-815

Keywords

Circular dichroism, Absolute configuration, Natural products