title: An epigenetic modifier induces production of (10'S)-verruculide B, an inhibitor of protein tyrosine phosphatases by Phoma sp. nov. LG0217, a fungal endophyte of Parkinsonia microphylla.
abstract: Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10'S)-verruculide B (1), vermistatin (2) and dihydrovermistatin (3). When cultured in the absence of the epigenetic modifier, it produced a new metabolite, (S,Z)-5-(3',4'-dihydroxybutyldiene)-3-propylfuran-2(5H)-one (4) together with nafuredin (5). The structure of 4 was elucidated by spectroscopic analyses and its absolute configuration was determined by application of the modified Mosher's ester method. The absolute structure of (10'S)-verruculide B was determined as 5-[(10'S,2'E,6'E)-10',11'-dihydroxy-3',7',11'-trimethyldodeca-2',6'-dien-1'-yl]-(3R)-6,8-dihydroxy-3-methylisochroman-1-one (1) with the help of CD and NOE data. Compound 1 inhibited the activity of protein tyrosine phosphatases (PTPs) 1B (PTP1B), Src homology 2-containing PTP 1 (SHP1) and T-cell PTP (TCPTP) with IC50values of 13.7±3.4, 8.8±0.6, and 16.6±3.8μM, respectively. Significance of these activities and observed modest selectivity of 1 for SHP1 over PTP1B and TCPTP is discussed.
authors.affiliation: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, AZ 85706, United States; NuBBE - Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais, Departamento de Química Orgânica, Instituto de Química, UNESP, Universidade Estadual Paulista, Araraquara, SP 14800-900, Brazil.
authors.forename: Juliana R
authors.initials: JR
authors.lastname: Gubiani
authors.affiliation: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, AZ 85706, United States.
authors.forename: E M Kithsiri
authors.initials: EM
authors.lastname: Wijeratne
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Taoda
authors.initials: T
authors.lastname: Shi
authors.affiliation: NuBBE - Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais, Departamento de Química Orgânica, Instituto de Química, UNESP, Universidade Estadual Paulista, Araraquara, SP 14800-900, Brazil.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Araujo
authors.affiliation: School of Plant Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: A Elizabeth
authors.initials: AE
authors.lastname: Arnold
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.affiliation: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, AZ 85706, United States. Electronic address: leslieg1@email.arizona.edu.
authors.forename: A A Leslie
authors.initials: AA
authors.lastname: Gunatilaka
mesh_terms: D001203:Ascomycota / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D007887:Fabaceae / Q000382:microbiology*; D009682:Magnetic Resonance Spectroscopy; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; C000606402:verruculide B; D017027:Protein Tyrosine Phosphatases
keywords: (10′S)-verruculide B; Epigenetic; Histone deacetylase inhibitor; Phoma sp. nov. LG0217; Protein tyrosine phosphatases