1-Deoxyrubralactone, a novel specific inhibitor of families X and Y of eukaryotic DNA polymerases from a fungal strain derived from sea algae

Abstract

Talaroflavone ( 1) and 1-deoxyrubralactone ( 2) are natural compounds isolated from cultures of a fungal strain derived from sea algae, and their structures were determined by spectroscopic analyses. Compound 2 is a novel rubralactone derivative, 6-hydroxy-8-methoxy-1-methyl-1,2,3 a,9 b-tetrahydrocyclopenta[ c]isochromene-3,5-dione. These compounds selectively inhibited the activities of families X and Y of eukaryotic DNA polymerases (pols), and compound 2 was a stronger inhibitor than compound 1. The IC 50 values of compound 2 on rat pol β, which is a pol of family X, and human pol κ, which is a pol of family Y, were 11.9 and 59.8 μM, respectively. On the other hand, compounds 1 and 2 did not influence the activities of the other families of eukaryotic pols, such as family A (i.e., pol γ) and family B (i.e., pols α, δ, and ε), and showed no effect even on the activities of plant pols α and β, prokaryotic pols, and other DNA metabolic enzymes, such as calf primase of pol α, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, mouse IMP dehydrogenase (type II), human topoisomerase I and II, T4 polynucleotide kinase, and bovine deoxyribonuclease I. This is the first report about the selective inhibitors of families X and Y of eukaryotic pols.