Atomic-Layer-Deposited SiOx/SnOx Nanolaminate Structure for Moisture and Hydrogen Gas Diffusion Barriers.

High-density SnOx and SiOx thin films were deposited via atomic layer deposition (ALD) at low temperatures (100 °C) using tetrakis(dimethylamino)tin(IV) (TDMASn) and di-isopropylaminosilane (DIPAS) as precursors and hydrogen peroxide (H2O2) and O2 plasma as reactants, respectively. The thin-film encapsulation (TFE) properties of SnOx and SiOx were demonstrated with thickness dependence measurements of the water vapor transmission rate (WVTR) evaluated at 50 °C and 90% relative humidity, and different TFE performance tendencies were observed between thermal and plasma ALD SnOx. The film density, crystallinity, and pinholes formed in the SnOx film appeared to be closely related to the diffusion barrier properties of the film. Based on the above results, a nanolaminate (NL) structure consisting of SiOx and SnOx deposited using plasma-enhanced ALD was measured using WVTR (H2O molecule diffusion) at 2.43 × 10-5 g/m2 day with a 10/10 nm NL structure and time-lag gas permeation measurement (H2 gas diffusion) for applications as passivation layers in various electronic devices.

6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE).

Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid ß (Aß) peptides and causes the accumulation of Aß in the brain. Moreover, recent studies suggest that the interactions between RAGE and Aß peptides may be the culprit behind Alzheimer's disease (AD). Inhibitors of the RAGE-Aß interactions would not only prevent the accumulation of toxic Aß in the brain, and but also block the progress of AD, therefore, have the potential to provide a 'disease-modifying therapy'. In this study, we have developed a series of 6-phenoxy-2-phenylbenzoxazole analogs as novel inhibitors of RAGE. Among these derivatives, we found several effective inhibitors that block the RAGE-Aß interactions without causing significant cellular toxicity. Further testing showed that compound 48 suppressed Aß induced toxicity in mouse hippocampal neuronal cells and reduced Aß levels in the brains of a transgenic mouse model of AD after oral administration.

The carbonate analogues of 5'-halogenated resiniferatoxin as TRPV1 ligands.

A series of carbonate analogues of 5'-halogenated RTX have been investigated in order to examine the effect of the carbonate group as a linker and the role of halogens in the reversal of activity from agonism to antagonism for rat and human TRPV1 heterologously expressed in Chinese hamster ovary cells. The carbonate analogues showed similar activities to the corresponding RTX derivatives in rat TRPV1 but lower potency in human TRPV1. 5-Halogenation converted the agonists to partial agonists or full antagonists and the extent of antagonism reflected the order of I>Br>Cl>F, with a somewhat greater extent of antagonism for the derivatives of the 4-amino RTX surrogates compared to the corresponding derivatives of RTX itself. The carbonate analogues of I-RTX (60) and 5-bromo-4-amino-RTX (66) were potent and full antagonists with Ki(ant)=2.23 and 2.46 nM, respectively, for rat TRPV1, which were ca. 5-fold more potent than I-RTX (2) under our conditions. The conformational analysis of the I-RTX-carbonate (60) indicated that its bent conformation was similar to that of I-RTX, consistent with compound 60 and I-RTX showing comparable potent antagonism.

Receptor activity and conformational analysis of 5'-halogenated resiniferatoxin analogs as TRPV1 ligands.

A series of 5'-halogenated resiniferatoxin analogs have been investigated in order to examine the effect of halogenation in the A-region on their binding and the functional pattern of agonism/antagonism for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Halogenation at the 5-position in the A-region of RTX and of 4-amino RTX shifted the agonism of parent compounds toward antagonism. The extent of antagonism was greater as the size of the halogen increased (I > Br > Cl > F) while the binding affinities were similar, as previously observed for our potent agonists. In this series, 5-bromo-4-amino RTX (39) showed very potent antagonism with K(i) (ant) = 2.81 nM, which was thus 4.5-fold more potent than 5'-iodo RTX, previously reported as a potent TRPV1 antagonist. Molecular modeling analyses with selected agonists and the corresponding halogenated antagonists revealed a striking conformational difference. The 3-methoxy of the A-region in the agonists remained free to interact with the receptor whereas in the case of the antagonists, the compounds assumed a bent conformation, permitting the 3-methoxy to instead form an internal hydrogen bond with the C4-hydroxyl of the diterpene.

Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin.

As an extension of our analysis of the effect of halogenation on thiourea TRPV1 agonists, we have now modified selected 4-hydroxy(or 4-amino)-3-methoxyphenyl acetamide TRPV1 agonists by 5- or 6-halogenation on the aromatic A-region and evaluated them for potency for TRPV1 binding and regulation and for their pattern of agonism/antagonism (efficacy). Halogenation shifted the functional activity at TRPV1 toward antagonism with a greater extent of antagonism as the size of the halogen increased (I>Br>Cl), as previously observed for the thiourea series. The extent of antagonism was greater for halogenation at the 5-position than at the 6-position, in contrast to SAR for the thiourea series. In this series, compounds 55 and 75 showed the most potent antagonism, with K(i) (ant)=2.77 and 2.19nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40-60-fold more potent than 6'-iodononivamide.