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

• Main Authors: Yoshiyuki Mizushina, Daisuke Manita, Toshifumi Takeuchi, Yuko Kumamoto-Yonezawa, Yuki Matsui, Fumio Sugawara, Masaharu Takemura, Hirosato Takikawa, Hiromi Yoshida, Mitsuru Sasaki
• Format: Article
• Language: English
• Published: MDPI AG 2008-12-01
• Series: Molecules
• Subjects: Kohamaic acid A (KA-A); DNA polymerase (DNA-directed DNA polymerase [E.C. 2.7.7.7]; pol); Enzyme inhibitor; Cytotoxicity; Computer simulation
• Online Access: http://www.mdpi.com/1420-3049/14/1/102/

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.