| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| 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.
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