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

Article Details

Citation

Copy to clipboard

Davis GC, Kong Y, Paige M, Li Z, Merrick EC, Hansen T, Suy S, Wang K, Dakshanamurthy S, Cordova A, McManus OB, Williams BS, Chruszcz M, Minor W, Patel MK, Brown ML

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

Bioorg Med Chem. 2012 Mar 15;20(6):2180-8. doi: 10.1016/j.bmc.2011.08.061. Epub 2011 Sep 1.

PubMed ID

22364743 [ View in PubMed

]

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. alpha-Hydroxy-alpha-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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Phenytoin	Sodium channel protein type 5 subunit alpha	IC 50 (nM)	>100000	N/A	N/A	Details