Novel autophagy modulators: Design and synthesis of (+)-epogymnolactam analogues and structure-activity relationship. Issue 18 (1st October 2018)

• Record Type: Journal Article
• Authors: Ueda, Kazuki; Okado, Yuji; Shigetomi, Kengo; Ubukata, Makoto
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 18(2018)
• Page Start: 5159
• Page End: 5168
• Publication Date: 2018-10-01
• Subjects: Epogymnolactam -- Autophagy inducer -- Autophagy inhibitor -- Structure activity relationship -- NIH3T3 cells; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.09.013
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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, and7 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 (2 R, 3 S )-epoxy group and cyclic syn -form (1b ) of1 are important for the activity as autophagy inducer. Hexyl analogue (8 ) as well as1 having butyl side-chain dose-dependently increased the ratio of LC3-II to LC3-I, whereas octyl analogue (9 ) and2 rather decreased the ratio. Decyl analogue (10 ) did not give a change in the ratio. Although8 seemed to be an excellent autophagy inducer, it dose-dependently increased SQSTM1 (p62) as in the case of2, whereas1 showed a slight dose-dependent decrease of p62 as an index of autophagic protein degradation. These observations suggest that8 is an autophagy modulator with different molecular target from1 or2 .