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Aplysiatoxin

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Hiroshi Nagai – One of the best experts on this subject based on the ideXlab platform.

  • neo Aplysiatoxin a isolated from okinawan cyanobacterium moorea producens
    Molecules, 2020
    Co-Authors: Mioko Kawaguchi, Masayuki Satake, Yueyun Xiao, Hajime Uchida, Botao Zhang, Masayuki Fukuoka, Hiroshi Nagai

    Abstract:

    A new Aplysiatoxin derivative, neo-Aplysiatoxin A (1), along with seven known compounds, neo-debromoAplysiatoxin A (2), dolastatin 3 (3), lyngbic acid (4), malyngamide M (5), hermitamide A (6), (−)-loliolide (7), and (+)-epiloliolide (8), was isolated from the Okinawan cyanobacterium Moorea producens. Their structures were elucidated on the basis of spectroscopic data, including high-resolution mass spectrometry and nuclear magnetic resonance. The compounds were evaluated for cytotoxic and diatom growth inhibition activities.

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  • Oscillatoxin I: A New Aplysiatoxin Derivative, from a Marine Cyanobacterium.
    Toxins, 2019
    Co-Authors: Hiroshi Nagai, Shingo Sato, Mioko Kawaguchi, Kazutaka Hayashi, Hajime Uchida, Kaori Iida, Masayuki Satake

    Abstract:

    Cyanobacteria have been shown to produce a number of bioactive compounds, including toxins. Some bioactive compounds obtained from a marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) have been recognized as drug leads; one of these compounds is Aplysiatoxin. We have isolated various Aplysiatoxin derivatives from a M. producens sample obtained from the Okinawan coastal area. The frozen sample was extracted with organic solvents. The ethyl acetate layer was obtained from the crude extracts via liquid-liquid partitioning, then separated by HPLC using a reversed-phase column. Finally, 1.1 mg of the compound was isolated. The chemical structure of the isolated compound was elucidated with spectroscopic methods, using HR-MS and 1D and 2D NMR techniques, and was revealed to be oscillatoxin I, a new member of the Aplysiatoxin family. Oscillatoxin I showed cytotoxicity against the L1210 mouse lymphoma cell line and diatom growth-inhibition activity against the marine diatom Nitzschia amabilis.

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  • new Aplysiatoxin derivatives from the okinawan cyanobacterium moorea producens
    Tetrahedron, 2019
    Co-Authors: Hiroshi Nagai, Minami Watanabe, Shingo Sato, Mioko Kawaguchi, Yueyun Xiao, Kazutaka Hayashi, Ryuichi Watanabe, Hajime Uchida, Masayuki Satake

    Abstract:

    Abstract The marine cyanobacterium Moorea producens is a rich source of diverse compounds that possess a variety of biological activities. In the present study, eight new Aplysiatoxin derivatives, namely 6, 8–13, and 15, along with Aplysiatoxin (1), debromoAplysiatoxin (2), 3-methoxyAplysiatoxin (3), anhydroAplysiatoxin (4), anhydrodebromoAplysiatoxin (5), oscillatoxin B2 (7), and 30-methyloscillatoxin D (14) were isolated and identified from the Okinawan M. producens. In cytotoxicity and diatom growth inhibition tests, the fifteen compounds tested (1–15) showed moderate or no activity at a concentration of 10 μg/mL.

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Kazuhiro Irie – One of the best experts on this subject based on the ideXlab platform.

  • Synthesis and biological activities of simplified Aplysiatoxin analogs focused on the CH/π interaction.
    Bioorganic & medicinal chemistry letters, 2020
    Co-Authors: Takumi Kobayashi, Ryo C. Yanagita, Kazuhiro Irie

    Abstract:

    Abstract DebromoAplysiatoxin (DAT) is a potent protein kinase C (PKC) activator with tumor-promoting and pro-inflammatory activities. Irie and colleagues have found that 10-methyl-aplog-1 (1), a simplified analog of DAT, has strong anti-proliferative activity against several cancer cell lines with few adverse effects. Therefore, 1 is a potential lead compound for cancer therapy. We synthesized a new derivative 2 which has a naphthalene ring at the side chain terminal position instead of a benzene ring, to increase CH/π interactions with Pro-241 of the PKCδ-C1B domain. Based on the synthetic route of 1, 2 was convergently synthesized in 26 linear steps from 6-hydroxy-1-naphthoic acid with an overall yield of 0.18%. Although the anti-proliferative activity of 2 was more potent than that of 1, the binding potency of 2 to the PKCδ-C1B domain did not exceed that of 1. Molecular dynamics simulation indicated the capability of 2 to simultaneously form hydrogen bonds and CH/π interactions with the PKCδ-C1B domain. Focusing on the hydrogen bonds, their geometry in the binding modes involving the CH/π interactions seemed to be sub-optimal, which may explain the slightly lower affinity of 2 compared to 1. This study could be of help in optimizing such interactions and synthesizing a promising lead cancer compound.

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  • Binding mode prediction of Aplysiatoxin, a potent agonist of protein kinase C, through molecular simulation and structure-activity study on simplified analogs of the receptor-recognition domain.
    Bioorganic & medicinal chemistry, 2016
    Co-Authors: Yoshiki Ashida, Ryo C. Yanagita, Chise Takahashi, Yasuhiro Kawanami, Kazuhiro Irie

    Abstract:

    Abstract Aplysiatoxin (ATX) is a naturally occurring tumor promoter isolated from a sea hare and cyanobacteria. ATX binds to, and activates, protein kinase C (PKC) isozymes and shows anti-proliferative activity against human cancer cell lines. Recently, ATX has attracted attention as a lead compound for the development of novel anticancer drugs. In order to predict the binding mode between ATX and protein kinase Cδ (PKCδ) C1B domain, we carried out molecular docking simulation, atomistic molecular dynamics simulation in phospholipid membrane environment, and structure–activity study on a simple acyclic analog of ATX. These studies provided the binding model where the carbonyl group at position 27, the hydroxyl group at position 30, and the phenolic hydroxyl group at position 20 of ATX were involved in intermolecular hydrogen bonding with the PKCδ C1B domain, which would be useful for the rational design of ATX derivatives as anticancer lead compounds.

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  • Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of Aplysiatoxin with anti-proliferative and cytotoxic activities.
    Bioscience biotechnology and biochemistry, 2015
    Co-Authors: Yusuke Hanaki, Harukuni Tokuda, Ryo C. Yanagita, Takahiro Sugahara, Misako Aida, Nobutaka Suzuki, Kazuhiro Irie

    Abstract:

    Aplog-1 is a simplified analog of the tumor-promoting Aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase Cδ (PKCδ) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (3), in which the C-1 ester group was replaced with an amide group, to improve chemical stability in vivo. Unfortunately, 3 exhibited seventy-fold weaker binding affinity to the C1B domain of PKCδ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10−4 M. A conformational analysis and density functional theory calculations indicated that the stable conformation of 3 differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (1, 2) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10−4 M, 3 may be an inactive control to identify the target proteins of aplogs.

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Masayuki Satake – One of the best experts on this subject based on the ideXlab platform.

  • neo Aplysiatoxin a isolated from okinawan cyanobacterium moorea producens
    Molecules, 2020
    Co-Authors: Mioko Kawaguchi, Masayuki Satake, Yueyun Xiao, Hajime Uchida, Botao Zhang, Masayuki Fukuoka, Hiroshi Nagai

    Abstract:

    A new Aplysiatoxin derivative, neo-Aplysiatoxin A (1), along with seven known compounds, neo-debromoAplysiatoxin A (2), dolastatin 3 (3), lyngbic acid (4), malyngamide M (5), hermitamide A (6), (−)-loliolide (7), and (+)-epiloliolide (8), was isolated from the Okinawan cyanobacterium Moorea producens. Their structures were elucidated on the basis of spectroscopic data, including high-resolution mass spectrometry and nuclear magnetic resonance. The compounds were evaluated for cytotoxic and diatom growth inhibition activities.

    Free Register to Access Article

  • Oscillatoxin I: A New Aplysiatoxin Derivative, from a Marine Cyanobacterium.
    Toxins, 2019
    Co-Authors: Hiroshi Nagai, Shingo Sato, Mioko Kawaguchi, Kazutaka Hayashi, Hajime Uchida, Kaori Iida, Masayuki Satake

    Abstract:

    Cyanobacteria have been shown to produce a number of bioactive compounds, including toxins. Some bioactive compounds obtained from a marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) have been recognized as drug leads; one of these compounds is Aplysiatoxin. We have isolated various Aplysiatoxin derivatives from a M. producens sample obtained from the Okinawan coastal area. The frozen sample was extracted with organic solvents. The ethyl acetate layer was obtained from the crude extracts via liquid-liquid partitioning, then separated by HPLC using a reversed-phase column. Finally, 1.1 mg of the compound was isolated. The chemical structure of the isolated compound was elucidated with spectroscopic methods, using HR-MS and 1D and 2D NMR techniques, and was revealed to be oscillatoxin I, a new member of the Aplysiatoxin family. Oscillatoxin I showed cytotoxicity against the L1210 mouse lymphoma cell line and diatom growth-inhibition activity against the marine diatom Nitzschia amabilis.

    Free Register to Access Article

  • new Aplysiatoxin derivatives from the okinawan cyanobacterium moorea producens
    Tetrahedron, 2019
    Co-Authors: Hiroshi Nagai, Minami Watanabe, Shingo Sato, Mioko Kawaguchi, Yueyun Xiao, Kazutaka Hayashi, Ryuichi Watanabe, Hajime Uchida, Masayuki Satake

    Abstract:

    Abstract The marine cyanobacterium Moorea producens is a rich source of diverse compounds that possess a variety of biological activities. In the present study, eight new Aplysiatoxin derivatives, namely 6, 8–13, and 15, along with Aplysiatoxin (1), debromoAplysiatoxin (2), 3-methoxyAplysiatoxin (3), anhydroAplysiatoxin (4), anhydrodebromoAplysiatoxin (5), oscillatoxin B2 (7), and 30-methyloscillatoxin D (14) were isolated and identified from the Okinawan M. producens. In cytotoxicity and diatom growth inhibition tests, the fifteen compounds tested (1–15) showed moderate or no activity at a concentration of 10 μg/mL.

    Free Register to Access Article