To date, all potent inhibitors against the mammalian Sec61 translocon are macrocyclic natural products. Among them, the ipomoeassin family of resin glycosides are structurally unique because they contain embedded carbohydrates as part of the ring framework. Interestingly, previous studies have shown that comparable to the parent natural product, ipomoeassin F, a couple of open-chain analogues also exhibited similar in vitro activities against cell growth and protein translocation. Because the ring-opened structure is more synthetically accessible, we hypothesize that it can be utilized to accelerate future chemical biology studies of the Sec61 translocon and the ipomoeassins for drug discovery. To support such hypothesis, we designed two simplified open-chain analogues of ipomoeassin F based on the most up-to-date structure–activity relationship (SAR) information. In this poster, we report our current progress towards chemical synthesis and biological evaluation of the two target molecules. Successful completion of the proposed studies will provide new knowledge on SAR, which can then be employed to develop novel chemical entities derived from ipomoeassin F to further investigate pharmaceutical potential of the Sec61 translocon.

Developing open-chain analogues of ipomoeassin F to evaluate pharmaceutical potential of the Sec61 translocon

ACS Fall 2021

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