title: Pyranicin, a non-classical annonaceous acetogenin, is a potent inhibitor of DNA polymerase, topoisomerase and human cancer cell growth.
abstract: This report describes the inhibitory activities of the natural and non-natural acetogenins [mucocin (compound 1), jimenezin (compound 2), 19-epi jimenezin (compound 3), muconin (compound 4), pyranicin (compound 5), pyragonicin (compound 6), 10-epi pyragonicin (compound 7), and a gamma-lactone (compound 8)], which were synthesized by us, against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compound 5 was revealed to be the strongest inhibitor of the animal pols and human topos tested, and the IC50 values for pols and topos were 2.3-15.8 and 5.0-7.5 microM, respectively. The compound also suppressed human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of pols and topos and the LD50 value was 9.4 microM. Compound 5 arrested the cells at G2/M and G1 phases, and prevented the incorporation of thymidine into the cells, indicating that it blocks DNA replication by inhibiting the activity of pols and topos. This compound also induced apoptosis of the cells. Based on these results, the action mode of compound 5 is discussed.
authors.affiliation: RIKEN (The Institute of Physical and Chemical Research), Wako-shi, Saitama, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yonezawa
authors.forename: Akemi
authors.initials: A
authors.lastname: Kubota
authors.forename: Narihito
authors.initials: N
authors.lastname: Ogawa
authors.forename: Katsuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshino
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakata
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D054378:Acetogenins / Q000378:metabolism*; D049109:Cell Proliferation; D026942:DNA Topoisomerases / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D016193:G1 Phase; D016195:G2 Phase; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000494:pharmacology*; D008956:Models, Chemical; D009369:Neoplasms / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors
chemical_list: D054378:Acetogenins; D004791:Enzyme Inhibitors; D005663:Furans; D007783:Lactones; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors; C475590:pyranicin; D004259:DNA-Directed DNA Polymerase; D026942:DNA Topoisomerases