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, w...
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2025-01-01
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| author | Arman Khosravi Precious Nnamdi Alexa May Kelsey Slattery Robert E. Sammelson Wei Q. Shi |
| author_facet | Arman Khosravi Precious Nnamdi Alexa May Kelsey Slattery Robert E. Sammelson Wei Q. Shi |
| author_sort | Arman Khosravi |
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| description | 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 (<b>10</b> and <b>11</b>); <b>10</b> without the C-4 carbonyl had a dramatic activity loss, whereas <b>11</b> 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, <b>11</b> can serve as a lead compound for developing future amino acid/peptide-modified analogues of Ipom-F with improved therapeutic properties. |
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| institution | Kabale University |
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| language | English |
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| spelling | doaj-art-2a9e2198ccb24870a722bb40be5941832025-01-24T13:43:55ZengMDPI AGMolecules1420-30492025-01-0130240010.3390/molecules30020400Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin FArman Khosravi0Precious Nnamdi1Alexa May2Kelsey Slattery3Robert E. Sammelson4Wei Q. Shi5Department of Chemistry, Ball State University, Muncie, IN 47306, USADepartment of Chemistry, Ball State University, Muncie, IN 47306, USAChemistry Department, Michigan State University, East Lansing, MI 48824, USADepartment of Chemistry, Ball State University, Muncie, IN 47306, USADepartment of Chemistry, Ball State University, Muncie, IN 47306, USADepartment of Chemistry, Ball State University, Muncie, IN 47306, USAIpomoeassin 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 (<b>10</b> and <b>11</b>); <b>10</b> without the C-4 carbonyl had a dramatic activity loss, whereas <b>11</b> 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, <b>11</b> can serve as a lead compound for developing future amino acid/peptide-modified analogues of Ipom-F with improved therapeutic properties.https://www.mdpi.com/1420-3049/30/2/400ipomoeassin Fresin glycosidesring-opened analoguescytotoxicitySec61 translocon |
| spellingShingle | Arman Khosravi Precious Nnamdi Alexa May Kelsey Slattery Robert E. Sammelson Wei Q. Shi Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F Molecules ipomoeassin F resin glycosides ring-opened analogues cytotoxicity Sec61 translocon |
| title | Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F |
| title_full | Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F |
| title_fullStr | Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F |
| title_full_unstemmed | Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F |
| title_short | Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F |
| title_sort | structural modifications reveal dual functions of the c 4 carbonyl group in the fatty acid chain of ipomoeassin f |
| topic | ipomoeassin F resin glycosides ring-opened analogues cytotoxicity Sec61 translocon |
| url | https://www.mdpi.com/1420-3049/30/2/400 |
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