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

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 K_i values of SCUL-B were calculated to be 1.8 and 6.8 μM for DNA polymerases α and γ, respectively. The K_i 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.