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Conditions to prepare trans-[Ru2(dmba)4(C[triple chemical bond]CAr)2] from [Ru2(dmba)4(NO(3))2] (DMBA=N,N'-dimethylbenzamidinate) and HC[triple chemical bond]CAr were optimized; Et2NH was found to be the most effective among a number of weak bases in facilitating the product formation. Furthermore, a series of unsymmetric trans-[(ArC[triple chemical bond]C)Ru(2)(dmba)4(C[triple chemical bond]CAr')] compounds were prepared under optimized conditions, in which one or both of Ar and Ar' are donor (NMe2)-/acceptor (NO(2))-substituted phenyls. While the X-ray crystallographic studies revealed a minimal structural effect upon donor/acceptor substitution, voltammetric measurements indicated a significant influence of substituents on the energy level of frontier orbitals. In particular, placing a donor and an acceptor on the opposite ends of trans-[(ArC[triple chemical bond]C)Ru2(dmba)4(C[triple chemical bond]CAr')] moiety results in an energetic alignment of frontier orbitals that favors a directional electron flow, a necessary condition for unimolecular rectification.

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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 hNav isoforms, human prostate cancer cells and xenograft. Enantiomers of lead demonstrated significant ability to reduce prostate cancer in vivo.

BackgroundApolipoprotein E (apoE) is postulated to affect brain Aβ levels through multiple mechanisms--by altering amyloid precursor protein (APP) processing, Aβ degradation, and Aβ clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo. Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and Aβ production.ResultsWe found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased Aβ levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer > dimer > monomer). We previously showed that the apoE dimer increased APP CTF in vivo; to determine whether the dimer also affected secreted APP or Aβ levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPPα and decreased Aβ levels at 24 hrs after treatment, suggesting that the apoE dimer may increase α-secretase cleavage.ConclusionsThese data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPPα and decreased Aβ levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and Aβ production both in vitro and in vivo.