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A mild and selective C(sp3)−H aerobic oxidation enabled by decatungstate photocatalysis has been developed. The reaction can be significantly improved in a microflow reactor enabling the safe use of oxygen and enhanced irradiation of the reaction mixture. Our method allows for the oxidation of both activated and unactivated C−H bonds (30 examples). The ability to selectively oxidize natural scaffolds, such as (−)‐ambroxide, pregnenolone acetate, (+)‐sclareolide, and artemisinin, exemplifies the utility of this new method.

Participation of p38 mitogen-activated protein kinase (p38) in insulin-induced glucose uptake was suggested using pyridinylimidazole p38 inhibitors (e.g. SB203580). However, the role of p38 in insulin action remains controversial. We further test p38 participation in glucose uptake using a dominant-negative p38 mutant and two novel pharmacological p38 inhibitors related to but different from SB203580. We present the structures and activities of the azaazulene pharmacophores A291077 and A304000. p38 kinase activity was inhibited in vitro by A291077 and A304000 (IC 50 ‫؍‬ 0.6 and 4.7 M). At higher concentrations A291077 but not A304000 inhibited JNK2␣ (IC 50 ‫؍‬ 3.5 M). Pretreatment of 3T3-L1 adipocytes and L6 myotubes expressing GLUT4myc (L6-GLUT4myc myotubes) with A291077, A304000, SB202190, or SB203580 reduced insulin-stimulated glucose uptake by 50 -60%, whereas chemical analogues inert toward p38 were ineffective. Expression of an inducible, dominant-negative p38 mutant in 3T3-L1 adipocytes reduced insulin-stimulated glucose uptake. GLUT4 translocation to the cell surface, immunodetected on plasma membrane lawns of 3T3-L1 adipocytes or on intact L6-GLUT4myc myotubes, was not altered by chemical or molecular inhibition of p38. We propose that p38 contributes to enhancing GLUT4 activity, thereby increasing glucose uptake. In addition, the azaazulene class of inhibitors described will be useful to decipher cellular actions of p38 and JNK.The p38 mitogen-activated protein kinases (p38), also referred to as stress-activated protein kinases-2, are a family of proline-directed serine/threonine kinases (1, 2). At least four isoforms, the products of different genes, have been cloned and are 60 -70% identical in their amino acid sequence. The most commonly used nomenclature of these isoforms are p38␣ (3, 4), p38␤ (5, 6), p38␥ (7,8), and p38␦ (9, 10). A splice variant of the p38␤, referred to as p38␤2, has also been described (11). Northern blot analysis has shown a wide tissue distribution of these isoforms, although p38␤ and p38␥ are preferentially expressed in skeletal muscle (5, 9). In addition to stressors, members of this family of protein kinases can also be activated by growth factors (12-15).Full activation of p38 by pro-inflammatory cytokines requires phosphorylation of Thr-180 and Tyr-182 found within a TGY tripeptide motif in the activation loop of the kinase (16). This double phosphorylation is catalyzed by the dual-specific MAPK 1 kinases MKK3 and MKK6 and possibly via auto-phosphorylation (17). It is remarkable that stimuli that increase p38 phosphorylation such as insulin-like growth factor-1 (18), muscle contraction (19 -21), lipoic acid (22), 5-aminoimidazole-4-carboxamide ribonucleoside (23), pro-inflammatory cytokines (18), protein synthesis inhibitors (24, 25), hyperosmolar stress (26), and preconditioning (ischemia/reperfusion) (27) also elevate glucose uptake. Importantly, the pyridinylimidazole inhibitor of p38, SB203580, reduced the stimulation of glucose uptake by all of the above stimuli incl...

Engagement of the T cell antigen receptor (TcR)1 with the antigen-major histocompatibility complex on antigen-presenting cells triggers a complex TcR signaling cascade that leads to T cell activation and cytokine secretion (1). During this process, T cells express the autocrine growth factor interleukin 2 (IL-2), which promotes T cell proliferation by interacting with the IL-2 receptor, which is also up-regulated on activated T cells. The transcriptional regulation of the IL-2 gene has been extensively analyzed at the IL-2 promoter, a 275-bp region located upstream of the transcriptional start site of the gene (2, 3). Several transcription factors have been identified to bind elements within this regulatory region, including AP-1, NF-B, and the nuclear factor of activated T cells (NFAT) (2).The transcription factor NFAT plays an essential role in IL-2 expression. Binding sites for NFATs have also been found within the promoter regions of several other cytokine genes, including IL-3, IL-4, IL-5, IL-8, IL-13, tumor necrosis factor ␣, granulocyte-macrophage colony-stimulating factor, and ␥-IFN (4, 5). NFAT is a complex composed of a cytoplasmic subunit and an inducible nuclear component comprised of AP-1 (Fos/ Jun) family members. At least four structurally related NFAT cytoplasmic subunit members, NFATp/NFAT1, NFATc/ NFAT2, NFAT3, and NFATX/NFATc3/NFAT4, have been identified (5). NFAT proteins share a conserved domain located toward the C terminus (6) that binds DNA and also participates in cooperative protein-protein interactions with AP-1 transcription factors (7,8). Immediately N-terminal to the DNA-binding domain is a second conserved module of ϳ300 residues known as the NFAT homology (NFAT-h) region. The N terminus of NFAT, including the NFAT-h region, regulates nuclear/cytoplasm trafficking in response to changes in intracellular Ca 2ϩ concentrations. In resting T cells, the protein is retained in the cytoplasm and its NFAT-h domain is heavily phosphorylated. Engagement of the TcR or treatment of cells with the Ca 2ϩ ionophore activates the Ca 2ϩ /calmodulin-dependent Ser/Thr phosphatase, calcineurin. CaN dephosphorylates the NFAT-h domain, resulting in translocation of NFAT to the nucleus (9).