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

Bioorg Med Chem. 2017 Mar 15;25(6):1860-1866. doi: 10.1016/j.bmc.2017.01.048. Epub 2017 Feb 3.

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 IC50 values 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.

Keywords: (10′S)-verruculide B; Epigenetic; Histone deacetylase inhibitor; Phoma sp. nov. LG0217; Protein tyrosine phosphatases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Ascomycota / drug effects*
  • Ascomycota / metabolism
  • Chromatography, High Pressure Liquid
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epigenesis, Genetic / drug effects*
  • Fabaceae / microbiology*
  • Magnetic Resonance Spectroscopy
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / metabolism*
  • Sesquiterpenes / pharmacology

Substances

  • Enzyme Inhibitors
  • Sesquiterpenes
  • verruculide B
  • Protein Tyrosine Phosphatases