Sebastian Baś

Synthesis of 2-Keto-d- and l-gluconic Acid via Stereoselective Direct Aldol Reactions

Stereoselective direct aldol reaction between optically pure d- or l-glyceraldehyde and hydroxyacetylfuran is demonstrated as an efficient and straightforward methodology for the synthesis of six-carbon atom d- and l-arabino-hex-2-ulosonic acids. syn-Selective aldol reactions realized by using either tertiary amines or a dizinc aldol catalyst constitute two parallel routes to the de novo synthesis of orthogonally protected biologically relevant 2-keto-d- and l-gluconic acids.

Organocatalytic Synthesis of Higher-Carbon Sugars: Efficient Protocol for the Synthesis of Natural Sedoheptulose and d-Glycero-l-galacto-oct-2-ulose.

Abstract Herein we report a short and efficient protocol for the synthesis of naturally occurring higher‐carbon sugars—sedoheptulose (d‐altro‐hept‐2‐ulose) and d‐glycero‐l‐galacto‐oct‐2‐ulose—from readily available sugar aldehydes and dihydroxyacetone (DHA). The key step includes a diastereoselective organocatalytic syn‐selective aldol reaction of DHA with d‐erythrose and d‐xylose, respectively. The methodology presented can be expanded to the synthesis of various higher sugars by means of syn‐selective carbon–carbon‐bond‐forming aldol reactions promoted by primary‐based organocatalysts. For example, this methodology provided useful access to d‐glycero‐d‐galacto‐oct‐2‐ulose and 1‐deoxy‐d‐glycero‐d‐galacto‐oct‐2‐ulose from d‐arabinose in high yield (85 and 74u2009%, respectively) and high stereoselectivity (99:1).

PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response

In recent years, phosphodiesterase (PDE) inhibitors have been frequently tested for the treatment of experimental inflammatory and immune disorders. It is suggested that anti-inflammatory properties of PDE inhibitors are related to their ability to increase cAMP levels. The aim of this study was to verify the hypothesis that cAMP may be a useful marker of pharmacological response following administration of non-selective PDE inhibitors (pentoxifylline and (±)-lisofylline) to endotoxemic rats. Male Wistar rats were administered LPS (1xa0mgxa0kg−1, i.v.) simultaneously with either compound given at two doses (40 and 80xa0mgxa0kg−1, i.v.). Levels of cAMP and both compounds in animal plasma were measured by the validated HPLC methods. Pharmacokinetic-pharmacodynamic analysis was performed using basic and modified indirect response (IDR) models II in Phoenix WinNonlin. The results of this study indicate that, in contrast to pentoxifylline, (±)-lisofylline demonstrates a non-linear pharmacokinetics in rats with endotoxemia. In vitro study using human recombinant PDE4B and PDE7A revealed the occurrence of additive interaction between studied compounds. Moreover, (±)-lisofylline is a more potent inhibitor of PDEs compared to pentoxifylline, as evidenced by lower IC50 values. Following administration of both compounds, levels of cAMP in rat plasma increased in a dose-dependent manner. The modified IDR model II better described cAMP levels over time profiles. The validity of the proposed marker was confirmed by measuring plasma TNF-α levels in the studied animals. In conclusion, cAMP may be used in future preclinical and clinical studies of some PDE inhibitors to evaluate the drug concentration–effect relationship.