Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues from Hydrocortisone via Hg(II)-Catalyzed Spiroketalization: Structure–Activity Relationship

Abstract

An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule 1 encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure-activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-β hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1.

Hippuristanol - A potent steroid inhibitor of eukaryotic initiation factor 4A

“…32 Eliminating the R 5 CH 3 group decreases activity approximately 5-8 fold, whereas increasing the bulkiness at R 5 decreases activity >15-fold. 109 The rank order of inhibition obtained in in vitro translation assays was similar to when several of the same congeners were assessed for direct inhibition of eIF4A RNA helicase activity 32 -consistent with eIF4A being the target through which hippuristanol exerts its inhibitory effects on protein synthesis. These results demonstrate that a large surface area of hippuristanol likely participates in binding to eIF4A.…”

“…Hippuristanol is a rare natural product and it was critical to develop synthetic routes to obtain sufficient material for biological studies as well as undertaking structure-activity relationship (SAR) studies. Four synthetic routes to hippuristanol have been published and used as starting material either hydrocortisone or hecogenin acetate/11-ketotigigenin [106][107][108][109] (Fig. 4A).…”

“…4A). These routes were employed to generate a number of analogs that have been tested for translation inhibition activity 106,109 and inhibition of cell proliferation against HeLa cells. 106 Taken together with data assessing the activity of several naturally occurring hippuristanol congeners in translation and eIF4A helicase activity, 32 we have a fairly good understanding of the essential features required for optimal hippuristanol activity ( Fig.…”

“…110 Appending functionalities onto R1 results in a 3-fold decrease in activity, whereas altering the R 2 OH leads to a 25-fold decrease in activity. 32,109 Converting the R 4 OH to a ketone or acetate diminishes activity approximately 25-and >2000 -fold, respectively. 32 Eliminating the R 5 CH 3 group decreases activity approximately 5-8 fold, whereas increasing the bulkiness at R 5 decreases activity >15-fold.…”

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…Additionally, the use of hippuristanol in vivo is limited by its relatively low solubility. Although synthetic derivatives have been generated [121][122][123] there has yet to be an equipotent analogue identified.…”