title: Total Synthesis and Biological Evaluation of Ipomoeassin F and Its Unnatural 11R-Epimer.
abstract: Ipomoeassin F, a macrolide glycoresin containing an embedded disaccharide, possesses potent in vitro antitumor activity with an unknown mechanism of function. It inhibits tumor cell growth with single-digit nanomolar IC50 values, superior to many clinical chemotherapeutic drugs. To facilitate translation of its bioactivity into protein function for drug development, we report here a new synthesis for the gram-scale production of ipomoeassin F (3.8% over 17 linear steps) from commercially available starting materials. The conformation-controlled subtle reactivity differences of the hydroxyl groups in carbohydrates were utilized to quickly construct the disaccharide core, which, along with judicial selection of protecting groups, made the current synthesis very efficient. The same strategy was also applied to the smooth preparation of the 11R-epimer of ipomoeassin F for the first time. Cytotoxicity assays demonstrated the crucial role of the natural 11S configuration. In addition, cell cycle analyses and apoptosis assays on ipomoeassin F and/or its epimer were conducted. This work has laid a solid foundation for understanding the medicinal potential of the ipomoeassin family of glycolipids in the future.
authors: Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors: Guanghui
authors: G
authors: Zong
authors: Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors: Eric
authors: E
authors: Barber
authors: Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors: Hazim
authors: H
authors: Aljewari
authors: Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors: Jianhong
authors: J
authors: Zhou
authors: Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors: Zhijian
authors: Z
authors: Hu
authors: Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors: Yuchun
authors: Y
authors: Du
authors: Department of Chemistry and Biochemistry and ‡Department of Biological Sciences, J. William Fulbright College of Arts & Science, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors: Wei Q
authors: WQ
authors: Shi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000737:chemistry; D006017:Glycolipids / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006001:Glycoconjugates; D006017:Glycolipids; C523857:ipomoeassin F