Total Synthesis and Biological Evaluation of Ipomoeassin F and Its Unnatural 11R-Epimer
| Autor: | Hazim Aljewari, Zhijian Hu, Yuchun Du, Wei Shi, Jianhong Zhou, Guanghui Zong, Eric Barber |
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| Rok vydání: | 2015 |
| Předmět: |
Molecular Structure
Chemistry Stereochemistry Organic Chemistry Disaccharide Total synthesis Antineoplastic Agents Apoptosis Stereoisomerism Cell cycle Article Structure-Activity Relationship chemistry.chemical_compound Biochemistry Cell Line Tumor Humans Structure–activity relationship Epimer Drug Screening Assays Antitumor Glycolipids Cytotoxicity Glycoconjugates Function (biology) |
| Zdroj: | The Journal of Organic Chemistry. 80:9279-9291 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/acs.joc.5b01765 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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