Inhibitory Effect of Acetogenins on Mammalian DNA Polymerase and Human Cancer Cell Growth

Chisato      Ishimaru; Toshifumi      Takeuchi; Yuko      Yonezawa; Isoko      Kuriyama; Msasaharu      Takemura; Ikuo      Kato; Fumio      Sugawara; Hiromi      Yoshida; Yoshiyuki      Mizushina

Abstract

Acetogenins from the Annonaceous plant are a fatty acid-derived natural product. We prepared the chemically synthesized natural acetogenins such as mucocin (compound 1), jimenezin (compound 2), muconin (compound 4), pyranicin (compound 5), and pyragonicin (compound 6). As related studies, 19-epi jimenezin (compound 3), 10-epi pyragonicin (compound 7), and a γ-lactone (compound 8), which is estimated to be a biosynthetic precursor of acetogenins, were also synthesized. Compounds 5 and 6 strongly inhibited, and compounds 1 - 4 and 7 moderately inhibited the activities of mammalian DNA polymerases (pols) such as replicative pol α and repair / recombination-related pol β. On the other hand, compound 8 did not influence the activities of any pols. Compound 5 was the strongest inhibitor of the pols tested, and the IC50 values for pols α and β were 5.3 and 9.6 μM, respectively. These compounds also suppressed human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of mammalian pols. Compound 5 was the strongest suppressor of the proliferation of HL-60 cells tested, and the LD50 value was 7.4 μM. The relationship between the three-dimensional molecular structure of acetogenins and these inhibitory activities is discussed.

Keywords: Acetogenins, Pyranicin, Enzyme inhibitor, DNA polymerase, Cytotoxicity, Computer simulation