Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F

Ipomoeassin F (Ipom-F) is a plant-derived macrocyclic resin glycoside that potently inhibits cancer cell growth through blockage of Sec61-mediated protein translocation at the endoplasmic reticulum. Recently, detailed structural information on how Ipom-F binds to Sec61α was obtained using Cryo-EM, which discovered that polar interactions between asparagine-300 (N300) in Sec61α and four oxygens in Ipom-F are crucial. One of the four oxygens is from the carbonyl group at C-4 of the fatty acid chain. In contrast, our previous structure-activity relationship (SAR) studies suggest that the carbonyl group is not essential. To resolve this discrepancy, we designed and synthesized two new open-chain analogues (10 and 11); 10 without the C-4 carbonyl had a dramatic activity loss, whereas 11 with an amide functional group was even more potent than Ipom-F. These new SAR data, in conjunction with some previous SAR information, imply two functional roles of the C-4 carbonyl: (1) to form H-bonds with N300; and (2) to regulate interactions of the fatty acid chain with membrane lipids. Impacts of these dual functions on antiproliferation depend on the overall structure of an Ipom-F derivative. Moreover, 11 can serve as a lead compound for developing future amino acid/peptide-modified analogues of Ipom-F with improved therapeutic properties.