Asymmetric reactions in water and in aqueous solutions have become an area of fast growing interest recently. Although for a long time neglected as a medium for organic reactions, water has attracted attention as the most widely distributed solvent in the world. Indeed, water is the solvent used by nature for biological chemistry including aldol reactions being essential for glycolysis, gluconeogenesis and related processes. Consequently, artificial catalysts designed and used for aldol reactions in water can be promising for the synthesis of enantiopure molecules and are also important for the understanding of complex chemistry of life. This tutorial review summarizes recent developments in the area of aqueous asymmetric aldol reactions highlighting two fundamental directions--development of water compatible chiral Lewis acids and amine-based organocatalysts.

The focused set of new pyrrolidine-2,5-diones as potential broad-spectrum hybrid anticonvulsants was described. These derivatives integrate on the common structural scaffold the chemical fragments of well-known antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. Such hybrids demonstrated effectiveness in two of the most widely used animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure models. Compound 33 showed the highest anticonvulsant activity in these models (ED MES = 79.5 mg/kg, ED 6 Hz = 22.4 mg/kg). Compound 33 was also found to be effective in pentylenetetrazole-induced seizure model (ED PTZ = 123.2 mg/kg). In addition, 33 demonstrated effectiveness by decreasing pain responses in formalin-induced tonic pain, in capsaicin-induced neurogenic pain, and notably in oxaliplatin-induced neuropathic pain in mice. The pharmacological data of stereoisomers of compound 33 revealed greater anticonvulsant activity by R(+)-33 enantiomer in both MES and 6 Hz seizure models.

Purpose This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. Methods Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. Results GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC 50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC 50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. Conclusions PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immunerelated diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

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The structures and magnetic properties of photoresponsive magnets can be controlled or fine-tuned by visible light irradiation, which makes them appealing as candidates for ternary memory devices: photochromic and photomagnetic at the same time. One of the strategies for photoresponsive magnetic systems is the use of photochromic/photoswitchable molecules coordinated to paramagnetic metal centers to indirectly influence their magnetic properties. Herein, we present two erbium­(III)-based coordination systems: a trinuclear molecule {[ErIII(BHT)3]3(dtepy)2}.4C5H12 (1) and a 1D coordination chain {[ErIII(BHT)3(azopy)} n ·2C5H12 (2), where the bridging photochromic ligands belong to the class of diarylethenes: 1,2-bis­((2-methyl-5-pyridyl)­thie-3-yl)­perfluorocyclopentene (dtepy) and 4,4′-azopyridine (azopy), respectively (BHT = 2,6-di-tert-butyl-4-methylphenolate). Both compounds show slow dynamics of magnetization, typical for single-molecule magnets (SMMs) as revealed by alternating current (AC) magnetic susceptibility measurements. The trinuclear compound 1 also shows an immediate color change from yellow to dark blue in response to near-UV irradiation. Such behavior is typical for the photoisomerization of the open form of the ligand into its closed form. The color change can be reversed by exposing the closed form to visible light. The chain-like compound 2, on the other hand, does not show significant signs of the expected trans–cis photoisomerization of the azopyridine in response to UV irradiation and does not appear to show photoswitching behavior.

Brønsted base−photocatalyst hybrid systems have been developed for reactions of malonates with styrene derivatives. The concept of this process lies in the photo-oxidation of catalytic amounts of the enolate to form reactive radicals that react with alkene double bonds under mild reaction conditions. This is an example of visible-light-activated C−C bond formation reactions of malonates with alkenes to realize high atom economy under very mild reaction conditions without using any transition-metal catalysts.

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 (1 mg kg−1, i.v.) simultaneously with either compound given at two doses (40 and 80 mg kg−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.