In vitro ion channel profile and ex vivo cardiac electrophysiology properties of the R(-) and S(+) enantiomers of hydroxychloroquine.

Hydroxychloroquine (HCQ) is a derivative of the antimalaria drug chloroquine primarily prescribed for autoimmune diseases. Recent attempts to repurpose HCQ in the treatment of corona virus disease 2019 has raised concerns because of its propensity to prolong the QT-segment on the electrocardiogram, an effect associated with increased pro-arrhythmic risk. Since chirality can affect drug pharmacological properties, we have evaluated the functional effects of the R(-) and S(+) enantiomers of HCQ on six ion channels contributing to the cardiac action potential and on electrophysiological parameters of isolated Purkinje fibers. We found that R(-)HCQ and S(+)HCQ block human Kir2.1 and hERG potassium channels in the 1 µM-100 µM range with a 2-4 fold enantiomeric separation. NaV1.5 sodium currents and CaV1.2 calcium currents, as well as KV4.3 and KV7.1 potassium currents remained unaffected at up to 90 µM. In rabbit Purkinje fibers, R(-)HCQ prominently depolarized the membrane resting potential, inducing autogenic activity at 10 µM and 30 µM, while S(+)HCQ primarily increased the action potential duration, inducing occasional early afterdepolarization at these concentrations. These data suggest that both enantiomers of HCQ can alter cardiac tissue electrophysiology at concentrations above their plasmatic levels at therapeutic doses, and that chirality does not substantially influence their arrhythmogenic potential in vitro.

Influence of Chirality of Lactones on the Perception of Some Typical Fruity Notes through Perceptual Interaction Phenomena in Bordeaux Dessert Wines.

Recent studies concerning the aroma of noble rot dessert wines revealed the importance of a well-known phenomenon in perfumery, the perceptual blending, to create the perception of "overripe orange" nuances. Thus, compounds associated with both oak wood aging (3-methyl-4-octanolide and eugenol) and Botrytis cinerea development under the form of noble rot (2-nonen-4-olide and γ-nonalactone) contribute to a specific aroma of great noble rot dessert wines through perceptual interaction phenomena. This synthetic perception phenomenon was established from reconstitution, addition, and omission sensory experiments, using wine extract fractions supplemented with the volatile compounds previously mentioned. To better understand the sensory impact of these compounds, the goal of this research was to study the contributions of enantiomeric forms of 2-nonen-4-olide and γ-nonalactone and the diastereoisomers of 3-methyl-4-octanolide. After multidimensional chiral chromatography analysis, the relative proportions of enantiomers or diastereomeric forms were first established and then sensory experiments were carried out using the reference compounds with isolated fractions from dessert wines. A dominance of the R form was established for 2-nonen-4-olide, which was correlated with wine aging, while the S form is more dominant in young dessert wines. Furthermore, the reconstitution experiments confirmed perceptual interaction phenomena and revealed the sensory contribution of (R)-2-nonen-4-olide and cis-3-methyl-4-octanolide concerning the "overripe orange" nuances, whereas no sensory impact for the γ-nonalactone isomers was observed.

Total Synthesis of Putative 11-epi-Lyngbouilloside Aglycon.

We report here the total synthesis of 11-epi-lyngbouilloside aglycon. Our strategy features a Boeckman-type esterification followed by a RCM to form the 14-membered ring macrolactone and a late-stage side chain introduction via a Wittig olefination. Overall, the final product was obtained in 20 steps and 2% overall yield starting from commercially available 3-methyl-but-3-enol. Most importantly, the strategy employed is versatile enough to eventually allow us to complete the synthesis of the natural product and irrevocably confirm its structure.

SAR156497, an exquisitely selective inhibitor of aurora kinases.

The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.