DNA Polymerase beta Specific Inhibitors, a Loliolide Derivative and Pubinernoid A, Isolated from the Brown Algae Laminaria sp.

Two mammalian DNA polymerase (pol) inhibitors have been isolated independently from the brown algae Laminaria sp. These molecules were determined by spectroscopic analyses to be a loliolide derivative, 2,3a-dihydroxy-4,4,6,7a- tetramethyl-3-oxo-octahydro-1-benzofuran-6-yl acetate (compound 1), and pubinernoid A (compound 2). Compounds 1 and 2 selectively inhibited the activity of rat pol beta, and 50% inhibition was observed at concentrations of 18.4 and 38.8 mu M, respectively. By contrast, these compounds did not influence the activity of 10 other mammalian pols [pols alpha, gamma, delta, epsilon, eta, iota, kappa, lambda, mu and terminal deoxynucleotidyl transferase (TdT)] tested, and showed no effect even on the activity of fish pol delta, plant pols alpha and lambda, prokaryotic pols, or any other DNA or RNA metabolic enzymes tested. Inhibition of rat pol beta activity by compounds 1 and 2 was competitive with both DNA template-primer and nucleotide substrate. The structure- activity relationship of these compounds is discussed.