A joint research group comprising Associate Professor Naoki Kato of the Faculty of Agriculture at Setsunan University, Professor Ryusuke Niwa of the Life Science Center for Survival Dynamics, at the Tsukuba Advanced Research Alliance (TARA), Associate Professor Yuuta Fujikawa of the School of Life Sciences at the Tokyo University of Pharmacy and Life Sciences (TUPLS), Professor Kazuhiko Matsuda of the Faculty of Agriculture at Kindai University, Unit Leader Hiroyuki Osada of the Chemical Resource Development Research Unit at the RIKEN Center for Sustainable Research Science, and Unit Leader Shunji Takahashi of the Natural Product Biosynthesis Research Unit at the RIKEN Center for Sustainable Research Science discovered that secondary metabolites produced by fungi (mold) can inhibit enzymes essential for insect growth. The finding is expected to help toward the development of agrochemicals for controlling insects. The results were published on August 31, 2023 in the international journal PLOS ONE.
The decalin-containing tetramic acids produced by fungi have diverse structural configurations owing to the tetramic acid moiety, the substituents on the decalin skeleton, and the steric configuration of decalin. Although various biological activities of these compounds have been reported, the structure−activity relationships based on the steric configurations of decalin have not been actively studied to date owing to difficulties in collecting and synthesizing the compounds.
The research group has successfully obtained decalin derivatives with various steric configurations, using genetically modified filamentous fungi in which the decalin synthase genes have been deleted or modified. In the present study, they examined the correlation between the biological activity and the steric configuration of the decalin compounds that they obtained. They evaluated the anticancer (cell growth inhibition), antibacterial, antifungal, antimalarial, and mitochondrial respiratory chain inhibitory activities of the compounds and found that the magnitude of the biological activities changed depending on the steric configuration of decalin.
Subsequently, the group hypothesized that the decalin compounds with different steric configurations might be useful not only for the evaluation of known bioactivities but also for searching unverified ones, and they investigated the inhibitory effect of the decalins against insect enzymes that have not been reported. Based on the structural similarity between decalin skeleton and ecdysteroids (steroid hormones found in insects), the researchers focused on the inhibitory activity against glutathione S-transferase Nobo (Noppera-bo), which is involved in ecdysteroid biosynthesis. They found that the cis-decalin derivatives had an inhibitory effect against this hormone.
Chemically synthesized insecticides are widely used to control agricultural pests, and the emergence of resistant insects has become problematic in recent years. A new type of pesticide that inhibits insect development and acts only on pests is an attractive target. Although the inhibitory activity of the decalin compounds is not as strong as that of known Noppera-bo inhibitors, the novel materials that the research group found provide a new framework for study. The researchers hope that the future co-crystal structural analysis of the Noppera-bo and cis-decalin compounds will lead to the development of more powerful pest control substances.
Publication: PLOS ONE
Title: cis-Decalin-containing tetramic acids as inhibitors of insect steroidogenic glutathione S-transferase Noppera-bo
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