Novel phenalenone derivatives from a marine-derived fungus exhibit. Distinct inhibition spectra against eukaryotic DNA polymerases

Marinela Perpelescu, Jun'ichi Kobayashi, Miho Furuta, Yasutomo Ito, Shunji Izuta, Masaharu Takemura, Motoshi Suzuki, Shonen Yoshida

研究成果: Article

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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 α and γ, moderately affected the activity of DNA polymerase ε, 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 β (IC50 = 17 μM), SCUL-B has only a weak influence upon this polymerase (IC50 = 90 μM). Kinetic studies showed that inhibition of both DNA polymerases α and β by either SCUL-A or SCUL-B was competitive with respect to dTTP substrate and noncompetitive with the template-primer. Whereas pol α 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 Ki values of SCUL-B were calculated to be 1.8 and 6.8 μM for DNA polymerases α and γ, respectively. The Ki of DNA polymerase β for SCUL-A was 12 μM and that for DNA polymerase α, 16 μM. Therefore, deletion of the OH-group at C12 enhanced inhibition of DNA polymerase β. 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.

元の言語English
ページ(範囲)7610-7616
ページ数7
ジャーナルBiochemistry
41
発行部数24
DOI
出版物ステータスPublished - 18-06-2002
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Biochemistry

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