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

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.

• Authors: 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
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 6 Pg. 2180-8 (Mar 15 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22364743 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Antineoplastic Agents
• Sodium Channel Blockers
• Sodium Channels

Topics

• Amides (chemical synthesis, chemistry, therapeutic use)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, therapeutic use)
• Cell Line
• Cell Line, Tumor
• Chemistry Techniques, Synthetic (methods)
• Humans
• Ion Channel Gating (drug effects)
• Isomerism
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Prostate (drug effects, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism)
• Sodium Channel Blockers (chemical synthesis, chemistry, therapeutic use)
• Sodium Channels (chemistry, metabolism)