title: 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.affiliation: University of Virginia, Department of Chemistry, Charlottesville, VA 22901, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Davis
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
authors.forename: Zhang
authors.initials: Z
authors.lastname: Li
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Merrick
authors.forename: Todd
authors.initials: T
authors.lastname: Hansen
authors.forename: Simeng
authors.initials: S
authors.lastname: Suy
authors.forename: Kan
authors.initials: K
authors.lastname: Wang
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Antoinette
authors.initials: A
authors.lastname: Cordova
authors.forename: Owen B
authors.initials: OB
authors.lastname: McManus
authors.forename: Brande S
authors.initials: BS
authors.lastname: Williams
authors.forename: Maksymilian
authors.initials: M
authors.lastname: Chruszcz
authors.forename: Wladek
authors.initials: W
authors.lastname: Minor
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007536:Isomerism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels