title: Novel phenalenone derivatives from a marine-derived fungus exhibit distinct inhibition spectra against eukaryotic DNA polymerases.
abstract: A number of compounds used for cancer chemotherapy exert their effects by inhibiting DNA replication. New inhibitors of DNA polymerases, therefore, could be potential candidates for new anti-cancer drugs. This study tested the effects of two phenalenone-skeleton-based compounds, which were isolated from a marine-derived fungus Penicillium sp., sculezonone-B (SCUL-B) and sculezonone-A (SCUL-A), upon DNA polymerase activity. Both compounds inhibited bovine DNA polymerases alpha and gamma, moderately affected the activity of DNA polymerase epsilon, and had almost no effect on HIV-reverse transcriptase and an E. coli DNA polymerase I Klenow fragment. Most notably, whereas SCUL-A inhibited pol beta (IC(50) = 17 microM), SCUL-B has only a weak influence upon this polymerase (IC(50) = 90 microM). Kinetic studies showed that inhibition of both DNA polymerases alpha and beta by either SCUL-A or SCUL-B was competitive with respect to dTTP substrate and noncompetitive with the template-primer. Whereas pol alpha inhibition by SCUL-B is competitive with respect to dATP, the inhibition by SCUL-A was found to be a mixed type with dATP substrate. The K(i) values of SCUL-B were calculated to be 1.8 and 6.8 microM for DNA polymerases alpha and gamma, respectively. The K(i) of DNA polymerase beta for SCUL-A was 12 microM and that for DNA polymerase alpha, 16 microM. Therefore, deletion of the OH-group at C12 enhanced inhibition of DNA polymerase beta. Since computational analyses of these two inhibitors revealed a remarkable difference in the distribution of negative electrostatic charge on the surface of molecules, we infer that different electrostatic charges might elicit different inhibition spectra from these two compounds.
authors.affiliation: Laboratory of Cancer Cell Biology, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Tsurumai 65, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Marinela
authors.initials: M
authors.lastname: Perpelescu
authors.forename: Jun'ichi
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Miho
authors.initials: M
authors.lastname: Furuta
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Ito
authors.forename: Shunji
authors.initials: S
authors.lastname: Izuta
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takemura
authors.forename: Motoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Shonen
authors.initials: S
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D049872:Bivalvia / Q000382:microbiology*; D002417:Cattle; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D010407:Penicillium / Q000737:chemistry*; D043803:Phenalenes; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry* / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D043803:Phenalenes; D011084:Polycyclic Aromatic Hydrocarbons; D011083:Polycyclic Compounds; C408002:sculezonone A; C408003:sculezonone B; C038036:phenalen-1-one; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D019951:DNA Polymerase beta; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase