Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity

Compounds that simultaneously activate peroxisome proliferator‐activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α‐ethoxyphenylpropionic acid bearing 5‐ or 6‐substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20 c and 21 a . Compound 20 c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21 a , less potent as a dual PPARα/γ activator than 20 c , showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.     

Concentration of thickening & gelling food additives by ultrafiltration: comparison of flat sheet and tubular membranes

Carrageenans and pectins are widely used for their rheological properties in many foods, as well as industrial applications. In their processing, Degussa Texturant Systems uses ultrafiltration as a concentration step. The aim of this study was to compare organic flat sheet and mineral tubular modules for carrageenan and pectin concentrations. Mineral tubular membranes led to higher flux performances than organic flat sheet membranes. The comparison of energy and membrane renewal costs did not make it possible to draw definitive conclusions on the choice between both modules. Nevertheless, subject to a life expectancy of more than ten years and to high operating times, mineral membranes should be more economic to operate.     

Multi-level Modeling of Silica–Template Interactions During Initial Stages of Zeolite Synthesis

Zeolite synthesis is driven by structure-directing agents, such as tetrapropyl ammonium ions (TPA⁺) for Silicalite-1 and ZSM-5. However, the guiding role of these organic templates in the complex assembly to highly ordered frameworks remains unclear, limiting the prospects for advanced material synthesis. In this work, both static ab initio and dynamic classical modeling techniques are employed to provide insight into the interactions between TPA⁺ and Silicalite-1 precursors. We find that as soon as the typical straight 10-ring channel of Silicalite-1 or ZSM-5 is formed from smaller oligomers, the TPA⁺ template is partially squeezed out of the resulting cavity. Partial retention of the template in the cavity is, however, indispensable to prevent collapse of the channel and subsequent hydrolysis.

Characterization of New PPARγ Agonists: Analysis of Telmisartan’s Structural Components

Telmisartan was originally designed as an AT₁ antagonist but was later also characterized as a selective PPARγ modulator. This study focused on the identification of the essential structural motifs of telmisartan for PPARγ activation activity, elucidating the individual SAR of each different component (shown).

     

Characterization of New PPARγ Agonists: Benzimidazole Derivatives – the Importance of Position 2

Probing SAR : The 1‐(biphenyl‐4‐ylmethyl)‐1H‐benzo[d]imidazole moiety is known to be an essential structural component of telmisartan for PPARγ activation. This study focused on the substituents at position 2 of the benzimidazole in an attempt to optimize PPARγ activation. In particular, the elongation of the alkyl chain and the introduction of an aromatic ring system were studied (shown).

     

Ecological Example of Conditioned Flavor Aversion in Plant–Herbivore Interactions: Effect of Terpenes of Eucalyptus Leaves on Feeding by Common Ringtail and Brushtail Possums

We investigated the hypothesis that feeding deterrence of common ringtail possums (Pseudocheirus peregrinus) and common brushtail possums (Trichosurus vulpecula) by Eucalyptus terpenes (in this case 1,8-cineole) is a result of a conditioned flavor aversion (CFA), due to the association of terpenes with postingestive effects of another group of Eucalyptus toxins, the diformylphloroglucinol compounds (DFPCs). Wild-caught common ringtail and common brushtail possums showed a dose-dependent reduction in food intake when 1,8-cineole was added to the diet. However, after continued exposure over 12 days to increasing amounts of cineole in the diet, both species substantially increased their intakes of cineole relative to control animals. This indicated that the aversion to cineole was a conditioned response rather than a physiological limitation in their ability to detoxify terpenes. Subsequent exposure to a diet including both cineole and jensenone (a simple DFPC also found in Eucalyptus and considered to cause postingestive emesis) in corresponding amounts was able to recondition the dose-dependent aversion. Consequently, animals that had been given jensenone showed an aversion to cineole-rich diets that matched the behavior of animals in the control group. This supported our hypothesis that the effect of terpenes on feeding of these marsupial folivores on Eucalyptus is due to a CFA. Possums can cope with levels of terpenes in the diet that far exceed those occurring naturally. The role of terpenes in marsupial folivore–Eucalyptus interactions appears to be to act as a cue to levels of toxic DFPCs in the leaves, rather than acting as toxins in their own right.     

Rigid cinchona conformers in enantioselective catalytic reactions: new cinchona‐modified platinum catalysts in the Orito reaction

The use of cinchona alkaloids (cinchonidine, cinchonine, quinine, quinidine, α-isocinchonine, α-isoquinidine, γ-isoquinidine) in the Orito reaction (hydrogenation of ethyl pyruvate and ethyl benzoylformate) strongly supports the structure of the intermediate complex (cinchona alkaloid “anti‐open” conformer–pyruvate 1 : 1 complex); in addition, so far unknown stereochemical conditions have been identified and the utilization of rigid cinchona conformers in the study of asymmetric syntheses have been generalized. This revised version was published online in July 2006 with corrections to the Cover Date.