title: Pinophilins A and B, inhibitors of mammalian A-, B-, and Y-family DNA polymerases and human cancer cell proliferation.
abstract: Pinophilins A (1) and B (2), new hydrogenated azaphilones, and Sch 725680 (3) were isolated from cultures of a fungus (Penicillium pinophilum Hedgcok) derived from a seaweed, and their structures were determined using spectroscopic analyses. These compounds selectively inhibited the activities of mammalian DNA polymerases (pols), A (pol γ), B (pols α, δ, and ε), and Y (pols η, ι, and κ) families, but did not influence the activities of the four X-family pols (pols β, λ, μ, and terminal deoxynucleotidyl transferase). Compound 1 was the strongest inhibitor, with IC₅₀ values of 48.6 to 55.6 μM. Kinetic analysis showed that compound 1 is a noncompetitive inhibitor of both pol α and κ activities with the DNA template-primer substrate, and a competitive inhibitor with the nucleotide substrate. In contrast, compounds 1-3 showed no effect on the activities of plant and prokaryotic pols or any other DNA metabolic enzymes tested. The compounds suppressed cell proliferation and growth in five human cancer cell lines, but had no effect on the viability of normal human cell lines.
authors.affiliation: Department of Applied Biological Science, Science University of Tokyo, Noda, Chiba 278-8510, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Myobatake
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ishido
authors.forename: Ken
authors.initials: K
authors.lastname: Hirano
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D049934:Isocoumarins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D019384:Nucleic Acid Synthesis Inhibitors; D010407:Penicillium / Q000737:chemistry*; D010860:Pigments, Biological / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D012624:Seaweed / Q000382:microbiology
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D049934:Isocoumarins; D019384:Nucleic Acid Synthesis Inhibitors; D010860:Pigments, Biological; C517257:Sch 725680; C494154:azaphilone; C571433:pinophilin A; C571434:pinophilin B; D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase