Penicilliols A and B, novel inhibitors specific to mammalian Y-family DNA polymerases

Bioorg Med Chem. 2009 Mar 1;17(5):1811-6. doi: 10.1016/j.bmc.2009.01.064. Epub 2009 Feb 1.

Abstract

Penicilliols A (1) and B (2) are novel 5-methoxy-3(2H)-furanones isolated from cultures of a fungus (Penicillium daleae K.M. Zalessky) derived from a sea moss, and their structures were determined by spectroscopic analyses. These compounds selectively inhibited activities of eukaryotic Y-family DNA polymerases (pols) (i.e., pols eta, iota and kappa), and compound 1 was a stronger inhibitor than compound 2. Among mammalian Y-family pols, mouse pol iota activity was most strongly inhibited by compounds 1 and 2, with IC(50) values of 19.8 and 32.5 microM, respectively. On the other hand, activities of many other pols, such as A-family (i.e., pol gamma), B-family (i.e., pols alpha, delta and epsilon) or X-family (i.e., pols beta, lambda and terminal deoxynucleotidyl transferase), and some DNA metabolic enzymes, such as calf primase of pol alpha, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, mouse IMP dehydrogenase (type II), human topoisomerases I and II, T4 polynucleotide kinase or bovine deoxyribonuclease I, are not influenced by these compounds. In conclusion, this is the first report on potent inhibitors of mammalian Y-family pols.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • DNA-Directed DNA Polymerase / chemistry
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Lactones / chemistry*
  • Lactones / isolation & purification
  • Lactones / pharmacology
  • Mice
  • Nucleic Acid Synthesis Inhibitors*
  • Penicillium / chemistry*

Substances

  • Enzyme Inhibitors
  • Lactones
  • Nucleic Acid Synthesis Inhibitors
  • penicilliol A
  • penicilliol B
  • DNA-Directed DNA Polymerase