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

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† Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant’Angelo, Via Cintia 4, 80126, Napoli, Italy
‡ Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium
§ Laboratoire Universitaire de Biodiversité et Ecologie Microbienne, University of Western Brittany, Avenue du Technopole, Plouzané, 29280 Brest, France
∥ Istituto di Scienze delle Produzioni Alimentari, Consiglio Nazionale delle Ricerche, Via Amendola 122/O, 70125 Bari, Italy
# Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Moruzzi 3, 56124 Pisa, Italy
⊥ Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas 78666, United States
*Tel: +39 081 2539178. E-mail: [email protected]
Cite this: J. Nat. Prod. 2016, 79, 1, 116–125
Publication Date (Web):December 23, 2015
https://doi.org/10.1021/acs.jnatprod.5b00779
Copyright © 2015 The American Chemical Society and American Society of Pharmacognosy
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    Abstract

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    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.

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