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Novel autophagy modulators: Design and synthesis of (+)-epogymnolactam analogues and structure-activity relationship
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| Title: | Novel autophagy modulators: Design and synthesis of (+)-epogymnolactam analogues and structure-activity relationship |
| Authors: | Ueda, Kazuki Browse this author | | Okado, Yuji Browse this author | | Shigetomi, Kengo Browse this author | | Ubukata, Makoto Browse this author →KAKEN DB |
| Keywords: | Epogymnolactam | | Autophagy inducer | | Autophagy inhibitor | | Structure activity relationship | | NIH3T3 cells |
| Issue Date: | 1-Oct-2018 |
| Publisher: | Elsevier |
| Journal Title: | Bioorganic & Medicinal Chemistry / Bioorganic and Medicinal Chemistry |
| Volume: | 26 |
| Issue: | 18 |
| Start Page: | 5159 |
| End Page: | 5168 |
| Publisher DOI: | 10.1016/j.bmc.2018.09.013 |
| Abstract: | (+)-Epogymnolactam (1) was discovered as a novel autophagy inducer from a culture of Gymnopus sp. in our laboratory. To determine structure-activity relationships among (+)-epogymnolactam analogues comparing with cerulenin (2), we synthesized 5 analogues including (-)-epogymnolactam (3) having each different functional group, and 3 analogues with different side-chain lengths. Five analogues, 3, 4, 5, 6, and 7 did not significantly increase the ratio of LC3-II to LC3-I as an autophagy marker in NIH3T3 cells. These results suggest that presence and stereochemistry of (2R, 3S)-epoxy group and cyclic syn-form (1b) of 1 are important for the activity as autophagy inducer. Hexyl analogue (8) as well as 1 having butyl side-chain dose-dependently increased the ratio of LC3-II to LC3-I, whereas octyl analogue (9) and 2 rather decreased the ratio. Decyl analogue (10) did not give a change in the ratio. Although 8 seemed to be an excellent autophagy inducer, it dosedependently increased SQSTM1 (p62) as in the case of 2, whereas 1 showed a slight dose-dependent decrease of p62 as an index of autophagic protein degradation. These observations suggest that 8 is an autophagy modulator with different molecular target from 1 or 2. |
| Rights: | © <2018>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ | | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/79390 |
| Appears in Collections: | 農学院・農学研究院 (Graduate School of Agriculture / Faculty of Agriculture) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 生方 信
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