Asymmetric synthesis and evaluation of a hydroxyphenylamide voltage-gated sodium channel blocker in human prostate cancer xenografts

Gary C. Davis, Yali Kong, Mikell Paige, Zhang Li, Ellen C. Merrick, Todd Hansen, Simeng Suy, Kan Wang, Sivanesan Dakshanamurthy, Antoinette Cordova, Owen B. McManus, Brande S. Williams, Maksymilian Chruszcz, Wladek Minor, Manoj K. Patel, Milton L. Brown

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Voltage-gated sodium channels are known to be expressed in neurons and other excitable cells. Recently, voltage-gated sodium channels have been found to be expressed in human prostate cancer cells. α-Hydroxy-α- phenylamides are a new class of small molecules that have demonstrated potent inhibition of voltage-gated sodium channels. The hydroxyamide motif, an isostere of a hydantoin ring, provides an active scaffold from which several potent racemic sodium channel blockers have been derived. With little known about chiral preferences, the development of chiral syntheses to obtain each pure enantiomer for evaluation as sodium channel blockers is important. Using Seebach and Frater's chiral template, cyclocondensation of (R)-3-chloromandelic acid with pivaldehyde furnished both the cis- and trans-2,5-disubsituted dioxolanones. Using this chiral template, we synthesized both enantiomers of 2-(3-chlorophenyl)-2-hydroxynonanamide, and evaluated their ability to functionally inhibit hNa v isoforms, human prostate cancer cells and xenograft. Enantiomers of lead demonstrated significant ability to reduce prostate cancer in vivo.

Original languageEnglish
Pages (from-to)2180-2188
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number6
DOIs
StatePublished - 15 Mar 2012
Externally publishedYes

Keywords

  • Frater-Seebach
  • Ion channel blocker
  • Prostate cancer

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