title: Cytotoxic epipolythiodioxopiperazine alkaloids from filamentous fungi of the Bionectriaceae.
abstract: Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a new dimeric epipolythiodioxopiperazine alkaloid, verticillin H (1), along with six related analogs, Sch 52900 (2), verticillin A (3), gliocladicillin C (4), Sch 52901 (5), 11'-deoxyverticillin A (6) and gliocladicillin A (7). The structures of compounds 1-7 were determined by extensive NMR and HRMS analyses, as well as by comparisons to the literature. All compounds (1-7) were evaluated for cytotoxicity against a panel of human cancer cell lines, displaying IC(50) values ranging from 1.2 μM to 10 nM. Compounds 1-5 were examined for activity in the NF-κB assay, where compounds 2 and 3 revealed activity in the sub-micromolar range. Additionally, compounds 1, 3 and 4 were tested for EGFR inhibition using an enzymatic assay, while compound 3 was examined against an overexpressing EGFR(+ve) cancer cell line.
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Figueroa
authors.forename: Tyler N
authors.initials: TN
authors.lastname: Graf
authors.forename: Sloan
authors.initials: S
authors.lastname: Ayers
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Adcock
authors.forename: David J
authors.initials: DJ
authors.lastname: Kroll
authors.forename: Jilai
authors.initials: J
authors.lastname: Yang
authors.forename: Steven M
authors.initials: SM
authors.lastname: Swanson
authors.forename: Ulyana
authors.initials: U
authors.lastname: Munoz-Acuna
authors.forename: Esperanza J
authors.initials: EJ
authors.lastname: Carcache de Blanco
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agrawal
authors.forename: Mansukh C
authors.initials: MC
authors.lastname: Wani
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Darveaux
authors.forename: Cedric J
authors.initials: CJ
authors.lastname: Pearce
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D006999:Hypocreales / Q000737:chemistry*; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013730:Terphenyl Compounds / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004220:Disulfides; D026121:Indole Alkaloids; D007211:Indoles; D016328:NF-kappa B; D010879:Piperazines; C097800:Sch 52900; D013730:Terphenyl Compounds; C555444:epipolythiodiketopiperazine; C009654:verticillins; D066246:ErbB Receptors; C540279:11,11'-dideoxyverticillin A