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 ground for understanding the medicinal potential of the ipomoeassin family of glycolipids in the future.

Synergistic Contribution of Tiglate and Cinnamate to Cytotoxicity of Ipomoeassin F

“…To elaborate further, in both strategies developed by Fürstner 10 and our group 11 , the tiglate moiety was introduced in a very early stage, which would make medicinal chemistry studies of the C-3-Glc p position inefficient. In contrast, the route adopted by Postema and coworkers could be the most suitable because tiglate was introduced at the penultimate step.…”

“…11 In this paper, we optimized the reaction conditions by changing the solvent to CH 2 Cl 2 . Besides the convenience in workup, it was a pleasure to find that the yield also slightly increased (74%, Scheme 2).…”

“…Besides the convenience in workup, it was a pleasure to find that the yield also slightly increased (74%, Scheme 2). The glucosyl donor 9 was prepared from commercially available D-glucose penta-acetate in 6 steps with an overall yield of 35% according to a procedure we developed earlier 11 . With both glucosyl donor 9 and fucoside acceptor 10 in hand, we then built the β-(1→2)-linked disaccharide 12 efficiently (80% over two steps) through regioselective glycosylation followed by acetylation of the remaining 4-OH-Glc p .…”

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).…”

“…6 From the diene intermediate 6a / b , ring-closing metathesis (RCM) and hydrogenation were still adopted to construct the saturated ring structure in 5a / b , to which cinnamate could be introduced, followed by removal of the TBS group, to give the desired monosaccharide analogues 3 and 4 . To control the β-linkage in 6a / b , the glucosyl donor 7 6 with Alloc as the neighboring participation group was chosen to couple with the alcohol acceptor 8a / b .…”