To date, several macrocyclic natural products including ipomoeassin F have been discovered to inhibit Sec61-mediated translocation of many membrane and secretory proteins in mammalian cells. Apparently, a ring scaffold seems to be the most pronounced common structural feature among these compounds; however, the ring size varies significantly, ranging from 12- to 30-membered ring. This raised an intriguing question about whether the nature has already selected the optimal ring size for each family of these molecules. To address this question, two ring-size-varying analogues of ipomoeassin F were synthesized and evaluated for their biological activities. Although decreasing the ring size from 20 to 19 caused more than 20-fold loss in cytotoxicity, increasing the ring size by 2 improved cytotoxicity by ~3-fold and in vitro protein translocation inhibition by ~2-fold. This delivers the encouraging message that there is unexplored chemical space in the binding pocket of Sec61α. Incorporation of new peripheral functionalities around the macrocyclic core of the ipomoeassin family of resin glycosides may lead to new chemical entities with further enhanced potency and even selectivity.

Ring expansion leads to a more potent analogue of ipomoeassin F

ACS Spring Meeting 2021

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