Expeditious Synthesis of Hippuristanol and Congeners with Potent Antiproliferative Activities

Abstract

Rapid access: An expeditious synthesis of hippuristanol was developed that allowed rapid access to a number of analogues with structural alteration at its E and F rings (see scheme), facilitating the structure–activity relationship studies of the novel inhibitor of eukaryotic translation initiation.

Modifying chemotherapy response by targeted inhibition of eukaryotic initiation factor 4A

“…19 Hipp's in vivo activity has not been significantly studied due to its limited availability, a shortcoming recently overcome by the elucidation of synthetic routes to its production. 21, 22 Herein, we show that Hipp is capable of reversing drug resistance in tumors engineered to be dependent on PI3K/AKT/mTOR signaling. These studies were extended to demonstrate that suppressing eIF4A activity sensitizes human lymphoma cells to Bcl-2 targeted therapies.…”

RNA helicases in infection and disease

“…All of these compounds are amenable to chemical synthesis. [232][233][234] Hippuristanol is an allosteric inhibitor of RNA binding to eIF4A. It shows a 10-fold increased specificity to eIF4A-I vs. eIF4A-III due to differences in the binding pockets, 158 demonstrating that selective pharmacological targeting of RNA helicases is possible.…”

Structural and stereochemical requirements of the spiroketal group of hippuristanol for antiproliferative activity

“…3 A key step in the synthesis entailed the addition of 2,3-dihydrofuran to a β-hydroxymethylketone precursor to construct the spiroketal functionality (Fig. 1).…”

“…3 In the present work, we decided to proceed, for most analogs, with structural “expansion”, i.e., increasing the ring size from five to six, adding an extra methyl group or enlarging the methyl groups to ethyl groups.…”