Total synthesis and SAR study of ipomoeassin F

by Zong, Guanghui; Aljewari, Hazim; Govindarajan, Mugunthan; Barber, Eric; Whisenhunt, Lucas; Shi, Wei

Ipomoeassins A-F, a family of macrolide glycoresin contg. an embedded disaccharide isolated from the leaves of Ipomoea squamosal, were found to possess potent in vitro antitumor activity with an unknown mechanism of function. More importantly, in the NCI 60-cell line screen, the naturally most abundant member of the family, ipomoeassin A, showed selective growth inhibition of different cancer cells, and its pattern of activity was clearly distinguished from other known anticancer agents based on a COMPARE anal. Therefore, it suggests that the ipomoeassins have novel mol. targets and can serve as promising new leads for developing a new class of anti-neoplastic agents. To identify their cellular targets for cancer therapeutics, ipomoeassin F was selected as a representative compd. in this venture because it showed the highest activity in the family. In this study, a new synthetic route for easy access to ipomoeassin F analogs with great structural variations was developed (3.8% over 17 linear steps, suitable for gram-scale synthesis). Initial structure-activity relationship (SAR) was studied and the results strongly suggest that the unsatd. esters on the carbohydrates were crucial to the cytotoxicity, while the ketone on the fatty acid chain was not a key factor. Open-chain ipomoeassin F analogs were also synthesized, some of which were still potent against several cancer cell lines but can be prepd. more efficiently because of avoiding ring closing metathesis step. Further SAR studies on the arom. ring in the cinnamate moiety successfully developed a potential chem. probe for future target identification of ipomoeassin F using chem. proteomics. This work represents a significant step forward in understanding the medicinal potential of the ipomoeassin family of glycolipids.