Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues via Suárez Cyclizations and Hg(II)-Catalyzed Spiroketalizations

Kontham, Ravindar; Reddy, Maddi Sridhar; Lindqvist, Lisa; Pelletier, Jerry; Deslongchamps, Pierre

doi:10.1021/jo102054r

Cited by 49 publications

(13 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Introductionmentioning

confidence: 88%

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

Cencic

Robert

Galicia-Vázquez

et al. 2013

Blood Cancer Journal

View full text Add to dashboard Cite

Translation is regulated predominantly at the initiation phase by several signal transduction pathways that are often usurped in human cancers, including the PI3K/Akt/mTOR axis. mTOR exerts unique administration over translation by regulating assembly of eukaryotic initiation factor (eIF) 4F, a heterotrimeric complex responsible for recruiting 40S ribosomes (and associated factors) to mRNA 5′ cap structures. Hence, there is much interest in targeted therapies that block eIF4F activity to assess the consequences on tumor cell growth and chemotherapy response. We report here that hippuristanol (Hipp), a translation initiation inhibitor that selectively inhibits the eIF4F RNA helicase subunit, eIF4A, resensitizes Eμ-Myc lymphomas to DNA damaging agents, including those that overexpress eIF4E—a modifier of rapamycin responsiveness. As Mcl-1 levels are significantly affected by Hipp, combining its use with the Bcl-2 family inhibitor, ABT-737, leads to a potent synergistic response in triggering cell death in mouse and human lymphoma and leukemia cells. Suppression of eIF4AI using RNA interference also synergized with ABT-737 in murine lymphomas, highlighting eIF4AI as a therapeutic target for modulating tumor cell response to chemotherapy.

show abstract

Section: Introductionmentioning

confidence: 88%

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

Cencic

Robert

Galicia-Vázquez

et al. 2013

Blood Cancer Journal

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Structure-activity Relationships Of Hippuristanolmentioning

confidence: 99%

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

Cencic

2016

Translation

Self Cite

View full text Add to dashboard Cite

Protein synthesis and its regulatory signaling pathways play essential roles in the initiation and maintenance of the cancer phenotype. Insight obtained over the last 3 decades on the mechanisms regulating translation in normal and transformed cells have revealed that perturbed control in cancer cells may offer an Achilles' heel for the development of novel anti-neoplastic agents. Several small molecule inhibitors have been identified and characterized that target translation initiationmore specifically, the rate-limiting step where ribosomes are recruited to mRNA templates. Among these, hippuristanol, a polyhydroxysteroid from the gorgonian Isis hippuris has been found to inhibit translation initiation by blocking the activity of eukaryotic initiation factor (eIF) 4A, an essential RNA helicase involved in this process. Herein, we highlight the biological properties of this compound, its potential development as an anti-cancer agent, and its use to validate eIF4A as an anti-neoplastic target.

show abstract

“…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.…”

Section: Hippuristanolmentioning

confidence: 99%