{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:39:19Z","timestamp":1759970359886,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T00:00:00Z","timestamp":1737158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences of the National Institutes of Health (NIH)","award":["GM116032"],"award-info":[{"award-number":["GM116032"]}]},{"name":"Ball State University","award":["GM116032"],"award-info":[{"award-number":["GM116032"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 Sec61\u03b1 was obtained using Cryo-EM, which discovered that polar interactions between asparagine-300 (N300) in Sec61\u03b1 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\u2013activity 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.<\/jats:p>","DOI":"10.3390\/molecules30020400","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T09:11:13Z","timestamp":1737364273000},"page":"400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6768-7132","authenticated-orcid":false,"given":"Arman","family":"Khosravi","sequence":"first","affiliation":[{"name":"Department of Chemistry, Ball State University, Muncie, IN 47306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Precious","family":"Nnamdi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ball State University, Muncie, IN 47306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexa","family":"May","sequence":"additional","affiliation":[{"name":"Chemistry Department, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey","family":"Slattery","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ball State University, Muncie, IN 47306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert E.","family":"Sammelson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ball State University, Muncie, IN 47306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5453-1753","authenticated-orcid":false,"given":"Wei Q.","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ball State University, Muncie, IN 47306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. 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