title: Higginsianins A and B, Two Diterpenoid α-Pyrones Produced by Colletotrichum higginsianum, with in Vitro Cytostatic Activity.
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.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo , Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Cimmino
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB) , Brussels, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Mathieu
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo , Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Masi
authors.affiliation: Laboratoire Universitaire de Biodiversité et Ecologie Microbienne, University of Western Brittany , Avenue du Technopole, Plouzané, 29280 Brest, France.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baroncelli
authors.affiliation: Istituto di Scienze delle Produzioni Alimentari, Consiglio Nazionale delle Ricerche , Via Amendola 122/O, 70125 Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Boari
authors.affiliation: Dipartimento di Chimica e Chimica Industriale, Università di Pisa , Via Moruzzi 3, 56124 Pisa, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pescitelli
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB) , Brussels, Belgium.
authors.forename: Marlène
authors.initials: M
authors.lastname: Ferderin
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB) , Brussels, Belgium.
authors.forename: Romana
authors.initials: R
authors.lastname: Lisy
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo , Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Evidente
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo , Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Tuzi
authors.affiliation: Istituto di Scienze delle Produzioni Alimentari, Consiglio Nazionale delle Ricerche , Via Amendola 122/O, 70125 Bari, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zonno
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University , San Marcos, Texas 78666, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kornienko
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB) , Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo , Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Evidente
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D020231:Colletotrichum / Q000737:chemistry*; D054697:Cytostatic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011753:Pyrones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014300:Trinidad and Tobago
chemical_list: D054697:Cytostatic Agents; D004224:Diterpenes; D011753:Pyrones; C000608587:higginsianin A; C000608588:higginsianin B