title: Depsides isolated from the Sri Lankan lichen Parmotrema sp. exhibit selective Plk1 inhibitory activity.
abstract: BACKGROUND
  Mitotic kinase enzymes regulate critical stages of mitosis and are amenable to pharmacological inhibition. Since natural products have been a rich source of antimitotic inhibitors, we postulated that natural products would also provide effective inhibitors of mitotic kinases.
  
  
  OBJECTIVE
  To explore unique marine and terrestrial natural product sources for new anticancer drug leads, we screened our natural product extract library for polo-like kinase-1 (Plk1) kinase inhibitors.
  
  
  METHODS
  Extracts of the lichen Parmotrema sp. (Parmeliaceae) exhibited in vitro inhibitory activity. Bioassay-guided fractionation of the Parmotrema sp. extract led to the isolation of depside inhibitors.
  
  
  RESULTS
  A new depside 1 has been isolated from the Sri Lankan lichen Parmotrema sp. along with the known metabolites 2 (β-collatolic acid) and 3 (β-alectoronic acid). The structure of depside 1 was elucidated by spectroscopic analysis. The three depsides 1-3 exhibited moderate inhibition of purified recombinant Plk1 kinase with IC₅₀ of 2.8, 0.7, and 1.7 µM, respectively, at 1 µM ATP. Inhibitory activity was also observed at high concentrations of ATP, suggesting the potential for activity in a cellular environment. The depsides were also tested against a panel of 23 other recombinant kinases and were found to possess up to 30-fold selectivity toward Plk1.
  
  
  CONCLUSIONS
  These data suggest that the depsides 1-3 may serve as core structures that can be further explored as potential inhibitors of Plk1 and other kinases.
authors.affiliation: Departments of Chemistry and Earth & Ocean Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Lauren
authors.initials: L
authors.lastname: Whitney
authors.forename: Jenny
authors.initials: J
authors.lastname: Togias
authors.forename: Richard
authors.initials: R
authors.lastname: Harrison
authors.forename: Maya P
authors.initials: MP
authors.lastname: Singh
authors.forename: Leonard A
authors.initials: LA
authors.lastname: McDonald
authors.forename: Selvaluxmy
authors.initials: S
authors.lastname: Kathirgamanathar
authors.forename: Veranja
authors.initials: V
authors.lastname: Karunaratne
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
mesh_terms: D000595:Amino Acid Sequence; D001203:Ascomycota; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053630:Depsides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D008011:Lichens; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013188:Sri Lanka; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D053630:Depsides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1