Synthesis of Thienopyrimidine Derivatives as Inhibitors of STAT3.

A series of thienopyrimidine compounds (6Aa-g and 6Ba-d) were synthesized and characterized by NMR spectroscopy and mass spectrometry. These compounds (6Aa-g and 6Ba-d) potently inhibited STAT3 expression induced by IL-6 in a dose-dependent manner with IC50 values of 5.73-0.32 µM. Among the prepared thienopyrimidine derivatives, 6Aa, 6Ab, 6Ba and 6Bc significantly suppressed the phosphorylation of STAT3 and ERK1/2 stimulated by IL-6 in Hep3B cells. Furthermore, the synthesized compounds might be useful remedies for the treatment of inflammatory diseases by inhibiting the action of IL-6.

A co-drug conjugate of naringenin and lipoic acid mediates neuroprotection in a rat model of oxidative stress.

Using our in vitro and in vivo models of oxidative stress, the current study was designed to determine the neuroprotective potential of naringenin, alone or in combination with lipoic acid. In our mixed neuronal culture exposed to hypoxia and subsequent reoxygenation, naringenin was shown to provide significant neuroprotection against cell death at a concentration of 2.5 µmol/L. Lipoic acid (LA) did not produce neuroprotection at any concentration tested (0.25-100 µmol/L). In contrast, when naringenin was covalently combined with LA, producing a novel compound named "VANL-100", significant neuroprotection was observed at a concentration as low as 2×10-2  µmol/L (100-fold more potent). An ELISA for antioxidant capacity demonstrated that naringenin and VANL-100 likely resulted in neuroprotection by increasing the free radical scavenging capacity of the neuronal cells. Pretreatment of rats with the above compounds prior to middle cerebral artery occlusion (MCAO) followed by reperfusion, showed similar results. Naringenin significantly reduced infarct volume at a dose of 10 mg/kg while VANL-100 produced significant neuroprotection at a dose as low as 1×10-4  mg/kg (10 000-fold more potent). This VANL-100-induced neuroprotection persisted even when administered 1 and 3 hours into the reperfusion time course. Taken together, these results suggest that our novel compound, VANL-100 is neuroprotective, likely via a mechanism that involves increasing the antioxidant capacity of neuronal cells. Our results also show that VANL-100 is 100-10 000-fold more potent than the parent compounds, which adds to the growing evidence in support of combination therapy targeting oxidative stress in neurodegenerative diseases.

Fenofibrate prevents obesity and hypertriglyceridemia in low-density lipoprotein receptor-null mice.

Our previous study demonstrated that fenofibrate improves both lipid metabolism and obesity, in part through hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) activation, in female ovariectomized, but not in sham-operated, low-density lipoprotein receptor-null (LDLR-null) mice. The aim of this study was to determine whether fenofibrate prevents obesity and hypertriglyceridemia in male LDLR-null mice. Mice fed a high-fat diet for 8 weeks exhibited increases in body and white adipose tissue (WAT) weights and developed severe hypertriglyceridemia compared with mice fed a low-fat control diet. However, these effects were effectively prevented by fenofibrate. Mice given a fenofibrate-supplemented high-fat diet showed significantly reduced body weight, WAT weight, and serum triglycerides versus high-fat diet-fed animals. Triton WR1339 study showed that fenofibrate-induced reduction in circulating triglycerides was due to the decreased secretion of triglycerides from the liver. Moreover, the administration of fenofibrate not only resulted in liver hypertrophy and reduction in hepatic lipid accumulation, but also regulated the transcriptional expression of PPARalpha target genes, such as hepatic acyl-coenzyme A (CoA) oxidase and apolipoprotein C-III (apoC-III). Therefore, our results suggest that alterations in hepatic PPARalpha action by fenofibrate seem to suppress diet-induced obesity and severe hypertriglyceridemia caused by LDLR deficiency in male mice.

Effect of a new beta-sitosterol analogue on plasma lipid concentrations in rats.

N-Substituted succinamic acid beta-sitosteryl ester derivatives were prepared and evaluated. Compounds 1 and 2 were prepared in 76-92% yields by the reaction of beta-sitosterol and succinic anhydride, followed by the activation of the resulting acid compound 1 by thionyl chloride or methyl chloroformate, and finally by amination with appropriate amines. Compound 2a (DANA87) was also easily obtained in one step by the direct addition of beta-sitosterol to dicyclohexylcarbodiimide (DCC) in 80% yield. Administration of the dietary compound DANA87 resulted in significant decreases in total plasma cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations compared with controls in a rat model. High-density lipoprotein cholesterol and plasma triglyceride levels were not affected. These findings indicate that DANA87 functions as TC and LDL cholesterol-reducing agent.