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.

Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency

“…Active agents, as ascertained by inhibition of pol β DNA synthesis activity in in vitro assays, have been discovered in extracts from bacteria, marine organisms, fungi and higher plants [91,[104][105][106][107][108][109]. Many of the "pol β inhibitory" compounds (glycoglycerolipids, sulfolipids, triterpenoids, phenalenone derivatives) have been found to inhibit other polymerases as well (e.g., DNA polymerases α, γ and λ, and HIV-1 reverse transcriptase) [110][111][112][113][114][115]. The primary aim given for these studies is the possibility of inhibiting repair of DNA adducts formed after treatment with DNA-damaging anticancer agents, and thus potentiating chemotherapeutic treatments.…”

Identification of Small Molecule Synthetic Inhibitors of DNA Polymerase β by NMR Chemical Shift Mapping

“…Many of the "␤-pol inhibitory" compounds (glycoglycerolipids, sulfolipids, triterpenoids, phenalenone derivatives) have been found to inhibit other polymerases as well (e.g. DNA polymerases ␣, ␥, and and HIV-1 reverse transcriptase) (15)(16)(17)(18)(19)(20); certain triterpenoid-derivative polymerase inhibitors were more recently found to also inhibit topoisomerases (21).…”

Fungal Phenalenones Inhibit HIV-1 Integrase

“…Therefore, 5 may be a good candidate lead compound for anti-HIV agent. Inhibition of DNA polymerases by the other phenalenones have been reported, but they did not inhibit HIV reverse transcriptase [19]. A plant metabolite, hypericin [20], is the only orthoand peri-fused aromatic compound reported to show integrase inhibition [21].…”