Cytotoxic epipolythiodioxopiperazine alkaloids from filamentous fungi of the Bionectriaceae

J Antibiot (Tokyo). 2012 Nov;65(11):559-64. doi: 10.1038/ja.2012.69. Epub 2012 Sep 12.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / isolation & purification
  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / isolation & purification*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Disulfides / chemistry
  • Disulfides / isolation & purification*
  • Disulfides / pharmacology*
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors
  • Humans
  • Hypocreales / chemistry*
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / isolation & purification*
  • Indole Alkaloids / pharmacology*
  • Indoles / chemistry
  • Indoles / isolation & purification
  • Indoles / pharmacology
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors
  • Piperazines / chemistry
  • Piperazines / isolation & purification*
  • Piperazines / pharmacology*
  • Terphenyl Compounds / chemistry
  • Terphenyl Compounds / isolation & purification*
  • Terphenyl Compounds / pharmacology*

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Disulfides
  • Indole Alkaloids
  • Indoles
  • NF-kappa B
  • Piperazines
  • Sch 52900
  • Terphenyl Compounds
  • epipolythiodiketopiperazine
  • verticillins
  • ErbB Receptors
  • 11,11'-dideoxyverticillin A