Asymmetric synthesis and evaluation of a hydroxyphenylamide voltage-gated sodium channel blocker in human prostate cancer xenografts
| Autor: | Owen B. McManus, Yali Kong, Sivanesan Dakshanamurthy, Wladek Minor, Ellen C. Merrick, Maksymilian Chruszcz, Todd P. Hansen, Brande S. Williams, Gary C. Davis, Kan Wang, Simeng Suy, Antoinette Cordova, Milton L. Brown, Manoj K. Patel, Zhang Li, Mikell Paige |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Models Molecular Stereochemistry Isostere Clinical Biochemistry Pharmaceutical Science Hydantoin Mice Nude Antineoplastic Agents Chemistry Techniques Synthetic Biochemistry Article Sodium Channels Cell Line chemistry.chemical_compound Mice Sodium channel blocker Isomerism Cell Line Tumor Drug Discovery Animals Humans Molecular Biology Mice Inbred BALB C Chemistry Sodium channel Organic Chemistry Enantioselective synthesis Prostate Prostatic Neoplasms Amides Cancer cell Molecular Medicine Enantiomer Ion Channel Gating Ion channel blocker Sodium Channel Blockers |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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