Structure and function of the novel autophagy inducer, (+)-epogymnolactam

2016 Fiscal Year Final Research Report

• Project/Area Number: 26450135
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bioorganic chemistry
• Research Institution: Hokkaido University
• Principal Investigator: Ubukata Makoto 北海道大学, 農学研究院, 特任教授 (60168739)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: オートファジー / エポジムノラクタム / 全合成 / 構造活性相関 / セルレニン

Outline of Final Research Achievements

To determine the structural requirement of (+)-epogymnolactam (1) for its autophagy-inducing activity, we first synthesized 1 in 8 steps. We next synthesized enantiomer of 1 ((-)-Epo), deepoxy derivative (Deepoxy), linear analog (N,N-Dimethyl), cyclic analog (O-Methyl), analog having C6 side chain (C6), analog having C8 side chain (C8). Structure-activity relationship in these compounds, synthetic intermediate (Amide 8), cerulean (Cer), and 1 indicated the importance of (2R,3S)-epoxy group, lactam structure, length of side chain, and presence or absence of double bond for their biological activities.
Cer inhibited autophagy in NIH 3T3 cells, and C6 and C8 analogs induced autophagy, whereas these two analogs inhibited the degradation of p62. These observations suggest that each molecular target for 1, Cer, and C6 or C8 should be different. The present study would contribute to the development of chemotherapeutic agents for the treatment of various incurable diseases.

Free Research Field

農学系創薬