Depsides isolated from the Sri Lankan lichen Parmotrema sp. exhibit selective Plk1 inhibitory activity

Abstract

Context: 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.

Materials and 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.

Discussion and conclusion: 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.

Keywords::

• Mitotic kinases
• purified recombinant Plk1 kinase
• differential activity