title: The inhibitory action of kohamaic acid A derivatives on mammalian DNA polymerase beta.
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 IC(50) values for mammalian pols was 3.22 to 8.76 microM; 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 beta 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 beta, and the binding energy between compound 11 and pol beta 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.
authors.affiliation: Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.forename: Daisuke
authors.initials: D
authors.lastname: Manita
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kumamoto-Yonezawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsui
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takemura
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sasaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hirosato
authors.initials: H
authors.lastname: Takikawa
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D011487:Protein Conformation; D013729:Terpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013729:Terpenes; C475030:kohamaic acid A; D019951:DNA Polymerase beta