The Inhibitory Action of Kohamaic Acid A Derivatives on Mammalian DNA Polymerase β

Abstract

We previously isolated a novel natural product, designated kohamaic acid A (KA-A, compound 1), as an inhibitor of the first cleavage of fertilized sea urchin eggs, and found that this compound could selectively inhibit the activities of mammalian DNA polymerases (pols). In this paper, we investigated the structure and bioactivity of KA-A and its chemically synthesized 11 derivatives (i.e., compounds 2–12), including KA-A - fatty acid conjugates. The pol inhibitory activity of compound 11 [(1S*,4aS*,8aS*)-17-(1,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-naphthalen-1-yl)heptadecanoic acid] was the strongest among the synthesized compounds, and the range of IC50 values for mammalian pols was 3.22 to 8.76 μM; therefore, the length of the fatty acid side chain group of KA-A is important for pol inhibition. KA-A derivatives could prevent human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of mammalian pols. Since pol β is the smallest molecule, we used it to analyze the biochemical relationship with KA-A derivatives. From computer modeling analysis (i.e., docking simulation analysis), these compounds bound selectively to four amino acid residues (Leu11, Lys35, His51 and Thr79) of the N-terminal 8-kDa domain of pol β, and the binding energy between compound 11 and pol β was largest in the synthesized compounds. The relationship between the three-dimensional molecular structures of KA-A-related compounds and these inhibitory activities is discussed.

DNA polymerases and cancer

“…Several small molecule inhibitors of POLβ have been found 168 , including some that can potentiate the toxic effects of the chemotherapeutic agents bleomycin 169 and temozolomide 170, 171 . Reduction of POLB expression also increases sensitivity to the chemotherapeutic agent oxaliplatin 172 .…”

Targeting DNA Polymerase ß for Therapeutic Intervention

“…The effect on cell division was suggested to proceed via a block or inhibition of sea urchin replication-essential DNA polymerases. More detailed analysis of KA-A and a series of analogs [88, 89] revealed broad spectrum inhibition of human DNA polymerases α, β, δ and γ, suggesting a possible universal mechanism of inhibition of DNA polymerases but a clear lack of specificity for Polβ. The structure of the natural compound KA-A and the most effective derivative [Compound #11; (1S*, 4aS*, 8aS*)−17-(1,4,4a,5,6,7,8,8a–octahydro-2,5,5,8a–tetramethylnaphthalen-1-yl)heptanoic acid] [88] is shown in Fig.…”

“…derived compound Kohamaic acid A (KA-A) and (B) the fatty acid derivative Compound #11; [1S*,4aS*,8aS*)-17-(1,4,4a,5,6,7,8,8a–octahydro-2,5,5,8a–tetramethylnaphthalen-1-yl)heptanoic acid] [88]. …”

Sesterterpenoids with Anticancer Activity

“…collected in Okinawa [70]. It was found to be a powerful DNA polymerase inhibitor [71], although it displayed only moderate cytotoxicity towards cancer cells [70]. …”