1-deoxyrubralactone, a novel specific inhibitor of families X and Y of eukaryotic DNA polymerases from a fungal strain derived from sea algae.
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-1,2,3a,9b-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 beta, which is a pol of family X, and human pol kappa, which is a pol of family Y, were 11.9 and 59.8 microM, 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 gamma) and family B (i.e., pols alpha, delta, and epsilon), and showed no effect even on the activities of plant pols alpha and beta, prokaryotic pols, and other 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 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.
Naganuma
Mitsuki
M
Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Nishida
Masayuki
M
Kuramochi
Kouji
K
Sugawara
Fumio
F
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D000818:Animals; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004259:DNA-Directed DNA Polymerase; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056890:Eukaryota / Q000382:microbiology*; D005658:Fungi / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D049934:Isocoumarins / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors; D051381:Rats; D013329:Structure-Activity Relationship; D000099270:Y-Family DNA Polymerases
D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase; D004791:Enzyme Inhibitors; D049934:Isocoumarins; D019384:Nucleic Acid Synthesis Inhibitors; C529436:1-deoxyrubralactone; C524963:rubralactone; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases