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Biosynthesis and Structure–Activity Relationship Studies of Okaramines That Target Insect Glutamate-Gated Chloride Channels
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-01-31 00:00:00 , DOI: 10.1021/acschembio.7b00878 Naoki Kato 1 , Shogo Furutani 1, 2 , Junnosuke Otaka 3 , Akira Noguchi 2 , Kiyomi Kinugasa 1 , Kenji Kai 4 , Hideo Hayashi 4 , Makoto Ihara 2 , Shunji Takahashi 1 , Kazuhiko Matsuda 2 , Hiroyuki Osada 3
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-01-31 00:00:00 , DOI: 10.1021/acschembio.7b00878 Naoki Kato 1 , Shogo Furutani 1, 2 , Junnosuke Otaka 3 , Akira Noguchi 2 , Kiyomi Kinugasa 1 , Kenji Kai 4 , Hideo Hayashi 4 , Makoto Ihara 2 , Shunji Takahashi 1 , Kazuhiko Matsuda 2 , Hiroyuki Osada 3
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Prenylated indole alkaloid okaramines selectively target insect glutamate-gated chloride channels (GluCls). Because of their highly complex structures, including azocine and azetidine rings, total synthesis of okaramine A or B has not been achieved, preventing evaluation of the biological activities of okaramines. Biosynthetic approaches provide alternatives to accessing structurally diverse derivatives and enabling the elucidation of structure–activity relationships. To explore the biosynthetic potential of okaramines, gene knockout experiments of an okaramine-producer fungus were performed. The deletion mutants of the oxygenase genes okaB, okaD, okaE, and okaG provided analogues that were unlikely to be accumulated in the normal biosynthetic process of the wild-type strain. Analysis of the structure–activity relationships of okaramines collected from the fungal cultures revealed that 1,4-dihydroazocine and N-aliphatic group attached to the indole were crucial for GluCl-activating activity. This provided insights into further derivatization of the complex structure of okaramines in order to facilitate the development of new insecticides.
中文翻译：
靶向谷氨酸门控氯离子通道的Okaramines的生物合成和结构-活性关系研究
烯丙基化的吲哚生物碱冈三胺选择性地靶向昆虫谷氨酸门控的氯离子通道（GluCls）。由于它们的高度复杂的结构（包括偶氮碱和氮杂环丁烷环），因此尚未实现冈卡拉明A或B的全合成，从而无法评估冈卡拉明的生物活性。生物合成方法为获取结构多样的衍生物提供了替代方法，并阐明了结构与活性之间的关系。为了探索冈果胺的生物合成潜力，进行了冈果胺生产菌的基因敲除实验。氧合酶基因okaB，okaD，okaE和okaG的缺失突变体提供了不太可能在野生型菌株的正常生物合成过程中积累的类似物。对从真菌培养物中收集的冈卡胺的结构-活性关系的分析表明，与吲哚相连的1,4-二氢偶氮cine嗪和N-脂族基团对GluCl激活活性至关重要。这提供了进一步了解冈他命胺的复杂结构衍生化的见识，以促进新型杀虫剂的开发。
更新日期：2018-01-31
中文翻译：
靶向谷氨酸门控氯离子通道的Okaramines的生物合成和结构-活性关系研究
烯丙基化的吲哚生物碱冈三胺选择性地靶向昆虫谷氨酸门控的氯离子通道（GluCls）。由于它们的高度复杂的结构（包括偶氮碱和氮杂环丁烷环），因此尚未实现冈卡拉明A或B的全合成，从而无法评估冈卡拉明的生物活性。生物合成方法为获取结构多样的衍生物提供了替代方法，并阐明了结构与活性之间的关系。为了探索冈果胺的生物合成潜力，进行了冈果胺生产菌的基因敲除实验。氧合酶基因okaB，okaD，okaE和okaG的缺失突变体提供了不太可能在野生型菌株的正常生物合成过程中积累的类似物。对从真菌培养物中收集的冈卡胺的结构-活性关系的分析表明，与吲哚相连的1,4-二氢偶氮cine嗪和N-脂族基团对GluCl激活活性至关重要。这提供了进一步了解冈他命胺的复杂结构衍生化的见识，以促进新型杀虫剂的开发。
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