Recently we discovered that the central metabolite α-ketoglutarate (α-KG) extends lifespan in C. elegans through inhibition of ATP synthase and TOR signaling. Unexpectedly, here we find that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG mediated processes, extends worm lifespan similarly. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase, and inhibit mTOR signaling; these effects are mirrored in IDH1 mutant cells, suggesting a growth suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, such as when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.

gamma-Aminobutyric acid type A receptors containing the alpha1 subunit participate in the inhibition of the righting reflexes by isoflurane and enflurane. They are not, however, involved in the amnestic effect of isoflurane or immobilizing actions of inhaled agents.

No abstract

Inhaled anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled anesthetics robustly enhance GABA A receptor (GABA A -R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABA A -Rs and individual GABA A -R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that inhaled anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABA A -Rs that harbor the ␣1 subunit. To test this, we used global knockout mice that completely lack the ␣1 subunit and forebrain-specific, conditional knockout mice that lack the ␣1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145% less sensitive to the amnestic effects of the inhaled anesthetic isoflurane. These results indicate that ␣1-containing GABA A -Rs in the hippocampus, amygdala, and/or cortex influence the amnestic effects of inhaled anesthetics and may be an important molecular target of the drug isoflurane.

3-Diazoindolin-2-imines were constructed from indoles and sulfonylazides via an electronically matched 1,3-dipolar cycloaddition and a subsequent dehydroaromatization/ring-opening cascade. The reaction between 3-substituted indoles and sulfonyl azides provided 2-aminoindoles, while 2-substituted indoles furnished 3-aminoindoles. Moreover, 2,3-diaminoindoles could be prepared from the resulting 3-diazoindolin-2-imines and secondary amines via a rhodium-catalyzed amination. Further extension of 2,3-diaminoindoles led to the formation of imidazo[4,5-b]indoles.

No abstract

3-Sulfonyl[1,2,3]triazolo[4,5-b]indoles were efficiently prepared via a tandem catalysis process involving intramolecular ligand stabilized CuAAC and Cu-catalyzed C-N coupling. The obtained 3-sulfonyl[1,2,3]triazolo[4,5-b]indoles could be utilized as α-imino rhodium carbene precursors for the construction of a range of valuable indole molecules including pyrrolo[2,3-b]indoles, spirocyclopropyl iminoindoles, 2,3-dihydropyrrolo[2,3-b]indoles, 3,3'-biindoles, and 2,3'-biindoles.

A series of novel pyrazolopyridine compounds have been designed and prepared by a general synthetic route. Their activities against the replication of poliovirus-1, EV-A71, and CV-B3 enteroviruses were evaluated. The comprehensive understanding of the structure-activity relationship was obtained by utilizing the variation of four positions, namely, N1, C6, C4, and linker unit. From the screened analogues, the inhibitors with the highest selectivity indices at 50% inhibition of viral replication (SI) were those with isopropyl at the N1 position and thiophenyl-2-yl unit at C6 position. Furthermore, the C4 position offered the greatest potential for improvement because many different N-aryl groups had better antiviral activities and compatibilities than the lead compound JX001. For example, JX040 with a 2-pyridyl group was the analogue with the most potent activity against non-polio enteroviruses, and JX025, possessing a 3-sulfamoylphenyl moiety, had the best activity against polioviruses. In addition, analogue JX037, possessing a novel pyrazolopyridine heterocycle, was also shown to have good antienteroviral activity, which further enlarges the compound space for antienteroviral drug design.