Revealing the Pharmacophore of Ipomoeassin F through Molecular Editing

Abstract

Ipomoeassin F, the flagship congener of a resin glycoside family exhibited single-digit nanomolar IC50 values against several cancer cell lines. To facilitate drug discovery based on this unique yet underexplored natural product, we performed the most sophisticated SAR studies of ipomoeassin F to date, which not only greatly bettered our understanding of its pharmacophore but also led to the discovery of two new derivatives (3 and 27) with similar potency but improved synthetic profile. The work presented here opens new avenues toward harnessing the medicinal potential of the ipomoeassin family of glycolipids in the future.

Synergistic Contribution of Tiglate and Cinnamate to Cytotoxicity of Ipomoeassin F

“…β-(1→2)-Linked disaccharide 12 was obtained by coupling glucosyl donor 9 9 and fucoside acceptor 10 followed by acetylation of the remaining 4- OH -Glc p according to our previously developed procedure. 9 CSA (261 mg, 1.12 mmol) was added in one portion to a solution of 12 (4.74 g, 5.62 mmol) in MeOH (50 mL) at room temperature.…”

“…9 CSA (261 mg, 1.12 mmol) was added in one portion to a solution of 12 (4.74 g, 5.62 mmol) in MeOH (50 mL) at room temperature. The reaction mixture was stirred for 3 h at which point TLC (silica, 1:1 EtOAc–hexanes) showed the starting material was gone.…”

“…In our previous effort to identify the pharmacophore of ipomoeassin F, we unambiguously demonstrated the critical roles of the two Michael acceptor systems. 9 Furthermore, one analogue ( 1 , Figure 1) in which cinnamate is replaced with tiglate showed a dramatic activity loss. Because our biological data indicated that cinnamate seemed to be more important for cytotoxicity than tiglate, 9 this raised a follow-up question regarding whether tiglate could be replaced with cinnamate.…”

“…9 Furthermore, one analogue ( 1 , Figure 1) in which cinnamate is replaced with tiglate showed a dramatic activity loss. Because our biological data indicated that cinnamate seemed to be more important for cytotoxicity than tiglate, 9 this raised a follow-up question regarding whether tiglate could be replaced with cinnamate. Would the two Michael systems have to be different, one aromatic and one aliphatic?…”

Design, synthesis and biological evaluation of fucose-truncated monosaccharide analogues of ipomoeassin F

“…6–8 During the studies, we found that two α,β-unsaturated esters in the (3-D-glucoside moiety, that is, cinnamate and tiglate (Table 1), are the most critical to the cytotoxicity of ipomoeassin F. On the other hand, modifications of the (3-D-fucoside moiety, 7 i.e. removal of the acetyl group from 4-OH-Fuc p (analogue 1, Table 1) or introduction of an acetyl group to 3-OH-Fuc p (analogue 2, Table 1), did not cause a dramatic cytotoxicity loss for the five tested cancer cell lines (2-23 fold loss for 1 and 2-14 fold loss for 2, respectively).…”