Structure-Function Correlations in the Mechanism of Action of Key Antiperspirant Agents Containing Al(III) and ZAG Salts.

Aluminum hydrolysis chemistry is an important part of modern society because of the dominance of Al(III) as a highly effective antiperspirant active. However, the century-old chemistry centered on aluminum chloride (ACL) is not comprehensive enough to address all of the in vivo events associated with current commercial antiperspirants and their mechanism of action. The present study aims to address the knowledge gap among extensively studied benchmark ACL, its modified version aluminum chlorohydrate (ACH), and a more complex but less explored group of aluminum zirconium chlorohydrate glycine complexes (ZAG salts) toward understanding the mechanism of action under consumer-relevant conditions. ACH, which is the Al source used in the manufacture of ZAG salts, provides a bridge between ACL and ZAG chemistry. High viscosity and gel formation driven by pH and a specific Al(III) salt upon hydrolysis are considered the criteria for building an in vivo occlusive mass to retard or stop the flow of sweat to the skin surface, thus providing an antiperspirant effect. Rheological studies indicated that ACL and aluminum zirconium tetrachlorohydrex glycine (TETRA) were the most efficacious salt actives. Spectroscopic studies, diffraction studies, and elemental analysis suggested that small metal oxide and hydroxide species with coparticipating glycine as well as various polynuclear and oligomeric species are the key to gel formation. At a given pH, the key ingredients (NaCl, urea, bovine serum albumin, and lactic acid) in artificial sweat were found to have little influence on Al(III) salt hydrolysis. The effects of the sweat components were mostly limited to local complex formation and kinetic modification. The in vitro comparative experiments with various Al(III) and ZAG salt systems offer unprecedented insights into the chemistry of different salt types, thus paving the way for engineering more efficacious antiperspirant systems.

Translating chemometric analysis into physiological insights from in vivo confocal Raman spectroscopy of the human stratum corneum.

The superficial layer of the skin, the stratum corneum (SC), consists of corneocytes surrounded by lipid regions and acts as a protective barrier for the body against water loss, toxic agents and microorganisms. As most substances permeate the stratum corneum through the lipid regions, lipid organization is considered crucial for the skin barrier function. Here, we investigate the potential of in vivo confocal Raman spectroscopy to describe the composition and organization of the SC. Confocal Raman spectroscopy is finding increasing use in the characterization of skin in biomedical, pharmaceutical and cosmetic applications. In this work, we analyze the spectra using chemometric methods and obtain principal components that correspond to the primary skin constituents: protein (keratin), natural moisturizing factor (NMF), water and lipid contributions in both ordered (orthorhombic) and disordered structural organization. By identifying these important components of the SC, these results highlight the utility of this in vivo, non-invasive, and depth resolved tool at the forefront of skin research.

Multimodal Evidence of Mesostructured Calcium Fatty Acid Deposits in Human Hair and Their Role on Hair Properties.

We provide the first conclusive evidence for the presence of exogenous calcium fatty acid deposits, which not only form in-between the cuticle layers in the lipid-rich cell membrane complex, but also grow to dimensions large enough to cause the structure to bulge, thereby impacting the optical and mechanical properties of the hair fiber. The composition and phase of these deposits were probed using a multimodal analytical approach with spatially resolved techniques including synchrotron micro X-ray fluorescence coupled with X-ray scattering, focused ion beam (FIB)-scanning electron microscopy (SEM), scanning transmission electron microscopy, X-ray energy dispersive spectroscopy, and Fourier transform infrared and Raman imaging where the collective analysis is consistent with a meso-phase composed of calcium C16/C18 saturated fatty acids from natural sources such as sebum. X-ray microtomography and serial "slice and view" FIB/SEM both reveal the location and volumetric shape of the deposits.

A General Synthesis of 4-Substituted 6-(2-Imidazolinylamino)-5,8-dimethylquinolines.

A general synthesis of 4-substituted 6-(2-imidazolinylamino)-5,8-dimethylquinolines 1 has been developed. All new compounds were synthesized from a common intermediate, 5,8-dimethyl-6-nitro-4-quinolone 3, the structure of which was confirmed by X-ray crystallography. This methodology involved the conversion of 3 into either a 4-chloro- or 4-bromoquinoline followed by the introduction of various 4-substituents late in the synthetic sequence. Substituents introduced in this way include alkyl (18a), alkoxy (12a, 12b), halo (9, 12c, 16), cyano (18b), thioalkyl (12d), acetamido (14), carboxamido (19), and hydroxy (10). This work illustrates the utility of 4-haloquinoline intermediates in the general synthesis of 4-substituted quinolines.

Synthesis and evaluation of (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones as Kv1.5 channel blockers for the treatment of atrial fibrillation.

A series of novel (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones were prepared and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation.

Synthesis and evaluation of novel 8,5-fused bicyclic peptidomimetic compounds as interleukin-1beta converting enzyme (ICE) inhibitors.

An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).