Ipomoeassin F is a natural product that acts as a potent inhibitor of the Sec61 complex responsible for the translocation of newly synthesised proteins into and across the membrane of the endoplasmic reticulum (ER). Our initial structure–activity relationship studies disclosed the essential role of the two α,β-unsaturated ester moieties, namely cinnamate and tiglate; however, it was proved that ipomoeassin F did not form a stable covalent adduct with its target protein, Sec61α. In this regard, we propose to introduce a cyano group to the α-position of cinnamate to enhance its electrophilicity, therefore strengthening the interaction between ipomoeassin F and Sec61α. We speculate that such modification would improve potency of the natural product for inhibiting Sec61-mediated protein translocation. In this poster, we report our current efforts to incorporate α-cyano cinnamic acids into a previously well-defined open-chain analogue as the surrogate of ipomoeassin F. The knowledge acquired from current synthesis and future biological evaluation of such analogues will facilitate development of novel chemical entities to further investigate pharmaceutical potential of the Sec61 translocon.

Design and synthesis of ipomoeassin F-derived Sec61 inhibitors containing α-cyano cinnamic acids

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ACS Fall 2022

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