Nodulisporol and Nodulisporone, novel specific inhibitors of human DNA polymerase λ from a fungus, Nodulisporium sp.

Tetralols 1 and 2, dihydroisocoumarins 3–6, and chromone 7 are natural compounds isolated from cultures of fungi, and their structures were determined by spectroscopic analyses. Compounds 1 and 2 from Nodulisporium sp. are novel tetralols, 1,2,3,4-tetrahydro-5-methoxynaphthalene-1,4-diol (nodulisporol) and 3,4-dihydro-4-hydroxy-8-methoxynaphthalen-1(2H)-one (nodulisporone), respectively. All isolated compounds selectively inhibited the activity of human DNA polymerase λ (pol λ), and compound 5 (3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarin) was the strongest inhibitor of pol λ in the tested compounds with an IC50 value of 49 μM. New tetralols (1 and 2) are the third and second strongest inhibitors of pol λ, but did not influence the activities of mammalian pols α to κ, and showed no effect even on the activities of plant pols α and β, prokaryotic pols, and other DNA metabolic enzymes such as calf terminal deoxynucleotidyl transferase, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, and bovine deoxyribonuclease I. The structure–activity relationships of isolated compounds such as novel tetralols, dihydroisocoumarins, and chromone are discussed.

Nodulisporol (1) and nodulisporone (2) are novel tetralols isolated from Nodulisporium sp., and they selectively inhibited the activity of human DNA polymerase λ.Figure optionsDownload as PowerPoint slide