title: Resorcylic acid lactones with cytotoxic and NF-κB inhibitory activities and their structure-activity relationships.
abstract: As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 63935; related to Phoma sp.). The initial extract exhibited cytotoxic activity against the H460 (human non-small cell lung carcinoma) and SF268 (human astrocytoma) cell lines and was selected for further study. Bioactivity-directed fractionation yielded resorcylic acid lactones (RALs) 1 (a new natural product) and 3 (a new compound) and the known RALs zeaenol (2), (5E)-7-oxozeaenol (4), (5Z)-7-oxozeaenol (5), and LL-Z1640-1 (6). Reduction of (5E)-7-oxozeaenol (4) with sodium borohydride produced 3, which allowed assignment of the absolute configuration of 3. Other known resorcylic acid lactones (7-12) were purchased and assayed in parallel for cytotoxicity with isolated 1-6 to investigate structure-activity relationships in the series. Moreover, the isolated compounds (1-6) were examined for activity in a suite of biological assays, including antibacterial, mitochondria transmembrane potential, and NF-κB. In the latter assay, compounds 1 and 5 displayed sub-micromolar activities that were on par with the positive control, and as such, these compounds may serve as a lead scaffold for future medicinal chemistry studies.
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, North Carolina 27402, United States.
authors.forename: Sloan
authors.initials: S
authors.lastname: Ayers
authors.forename: Tyler N
authors.initials: TN
authors.lastname: Graf
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Adcock
authors.forename: David J
authors.initials: DJ
authors.lastname: Kroll
authors.forename: Susan
authors.initials: S
authors.lastname: Matthew
authors.forename: Esperanza J
authors.initials: EJ
authors.lastname: Carcache de Blanco
authors.forename: Qi
authors.initials: Q
authors.lastname: Shen
authors.forename: Steven M
authors.initials: SM
authors.lastname: Swanson
authors.forename: Mansukh C
authors.initials: MC
authors.lastname: Wani
authors.forename: Cedric J
authors.initials: CJ
authors.lastname: Pearce
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D005658:Fungi / Q000737:chemistry; D006801:Humans; D062385:Hydroxybenzoates / Q000737:chemistry; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D012118:Resorcinols; D013329:Structure-Activity Relationship; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000008:administration & dosage
chemical_list: C505734:7-oxozeanol; D000900:Anti-Bacterial Agents; D062385:Hydroxybenzoates; D007783:Lactones; D016328:NF-kappa B; D012118:Resorcinols; C076950:alpha-resorcylic acid; D015025:Zearalenone