Total Synthesis and Biological Evaluation of Ipomoeassin F and Its Unnatural 11R-Epimer

The Journal of Organic Chemistry
Guanghui ZongWei Q Shi

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.

References

Oct 31, 2003·Bioscience, Biotechnology, and Biochemistry·Masashi IshikawaTakeshi Kitahara
Jan 27, 2007·Journal of the American Chemical Society·Alois Fürstner, Takashi Nagano
May 8, 2008·The Journal of Organic Chemistry·David G I Kingston
Feb 21, 2009·Organic Letters·Maarten H D PostemaQunli Xu
Aug 22, 2009·Chemistry : a European Journal·Takashi NaganoAlois Fürstner
Mar 26, 2011·Current Medicinal Chemistry·P DeF Bedos-Belval
Jun 18, 2011·The Journal of Organic Chemistry·Ophélie MilhommeCyrille Grandjean
Apr 17, 2012·Natural Product Reports·Malte GerschStephan A Sieber
Jul 10, 2014·Chemical Reviews·Juan Xie, Nicolas Bogliotti

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Citations

Mar 22, 2016·Organic Letters·Guanghui ZongWei Q Shi
Mar 8, 2018·Natural Product Reports·Jacob RodriguezMaciej A Walczak
Sep 25, 2019·Chemistry, an Asian Journal·Shoji KobayashiAraki Masuyama
Feb 9, 2021·The Journal of Organic Chemistry·Stefanie MayrHendrik Zipse
Jan 13, 2021·Journal of Natural Products·David G I Kingston
Jan 2, 2018·European Journal of Medicinal Chemistry·Guanghui ZongWei Q Shi
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Surya B AdhikariGuijun Wang
Apr 11, 2017·The Journal of Organic Chemistry·Guanghui ZongWei Q Shi
Dec 3, 2020·The Journal of Organic Chemistry·Guanghui ZongWei Q Shi
May 7, 2019·Journal of the American Chemical Society·Guanghui ZongWei Q Shi
Sep 25, 2021·Journal of Cell Science·Pawel LeznickiStephen High
Oct 26, 2021·Chemistry : a European Journal·Stefanie Mayr, Hendrik Zipse
Jul 3, 2021·Communications Biology·Sarah O'KeefeStephen High

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