Like other potent inhibitors against the mammalian Sec61 translocon, the ipomoeassin family of resin glycosides are macrocyclic natural products with an embedded disaccharide core as part of the ring framework. Despite optimized synthesis, intramolecular ring closure remains a scale-limiting step because diluted concentration is required to minimize competing intermolecular side reactions. Interestingly, previous studies demonstrated that compared with the parent natural product, ipomoeassin F, a couple of open-chain analogues also exhibited similar in vitro activities against cell growth and protein translocation. Attracted by its greater synthetic accessibility, we carried out systematic studies to prove our hypothesis that the ring-opened structure is a feasible surrogate that can be utilized to accelerate future chemical biology studies of the Sec61 translocon and the ipomoeassins for drug discovery. In this poster, we report our current efforts in biological assessment, computational simulation, and chemical synthesis towards an active simplified analogue of ipomoeassin F. The knowledge acquired from such studies will facilitate future development of novel chemical entities to further investigate pharmaceutical potential of the Sec61 translocon.

Biology-directed and in silico-aided rational design leads to an active simplified “4-in-1” analogue of ipomoeassin F

ACS Spring 2022

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