Resorcylic acid lactones with cytotoxic and NF-κB inhibitory activities and their structure-activity relationships

J Nat Prod. 2011 May 27;74(5):1126-31. doi: 10.1021/np200062x. Epub 2011 Apr 22.

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.

Publication types

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

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Fungi / chemistry
  • Humans
  • Hydroxybenzoates / chemistry
  • Lactones / chemistry
  • Lactones / isolation & purification*
  • Lactones / pharmacology*
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors*
  • Resorcinols
  • Structure-Activity Relationship
  • Zearalenone / analogs & derivatives*
  • Zearalenone / chemistry
  • Zearalenone / pharmacology

Substances

  • 5-7-oxo-zeaenol
  • Anti-Bacterial Agents
  • Hydroxybenzoates
  • Lactones
  • NF-kappa B
  • Resorcinols
  • alpha-resorcylic acid
  • Zearalenone