No abstract

a n aldol condensation product. In the presence of phosphorylating system, the phosphorus appears principally a s inorganic phosphate, presumably by reaction with t h e water produced in the selfcondensation of pyruvate. Acknowledgment. We gratefully acknowledge t h e support of this investigation by t h e National Science Foundation. Registry No. I, Abstract:The Beckmann rearrangement of oxime sulfonates with simultaneous nucleophilic trapping of the intermediary iminocarbocation by organoaluminum reagents is described. This process provides a new and highly efficient route to imino thioethers, imino selenoethers, imino nitriles, and a-alkylated amines starting from oxime sulfonates by the use of dialkylaluminum thiolates, selenolates, diethylaluminum chloride-trimethylsilyl cyanide, and trialkylaluminum-diisobutylaluminum hydride systems, respectively. The present organoaluminum-promoted Beckmann rearrangement of oxime sulfonates has been successfully applied to the synthesis of naturally occurring alkaloids, pumiliotoxin C and solenopsin A and B, in stereoselective fashion.Moreover, a,a-dialkylation of amines can be realized by the successive treatment of oxime sulfonates with trialkylaluminum followed by allylic or propargylic Grignard reagents in synthetically useful yields.(4) For a review of aluminum reagents, see: Yamamoto, H.; Nozaki, H.

Recent data have shown that TLR4 performs a key role in cerebral ischemia-reperfusion injury which serves as the origin of the immunological inflammatory reactions. However, the therapeutic effects of pharmacological inhibitions of TLR4 and its immediate down-stream pathway remain to be uncovered. In the present study, on mice, intracerebroventricular injection of resatorvid (TLR4 signal inhibitor; 0.01 μg) significantly reduced infarct volume and improved neurological score after middle cerebral artery occlusion and reperfusion. The levels of phospho-p38, nuclear factor-kappa B, and matrix metalloproteinase 9 expressions were significantly suppressed in the resatorvid-treated group. In addition, NOX4 associates with TLR4 after cerebral ischemia-reperfusion seen in mice and human. Genetic and pharmacological inhibitions of TLR4 each reduced NOX4 expression, leading to suppression of oxidative/nitrative stress and of neuronal apoptosis. These data suggest that resatorvid has potential as a therapeutic agent for stroke since it inhibits TLR4-NOX4 signaling which may be the predominant causal pathway.

Triostin A is a biosynthetic precursor of echinomycin which is one of the most potent hypoxia inducible factor 1 (HIF-1) inhibitors. An improved solution-phase synthesis of triostin A on a preparative scale has been achieved in 17.5% total yield in 13 steps. New analogues of triostin A with various aromatic chromophores, oxidized intra-peptide disulfide bridges and diastereoisomeric cyclic depsipeptide cores were also successfully synthesized. All analogues had a significant inhibitory effect on HIF-1 transcriptional activation in hypoxia and cytotoxicity on MCF-7 cells, with the exception of the derivatives containing a naphthalene chromophore or a thiosulfonate bridge. For the first time, triostin A, echinomycin and the thiosulfinate analogue of triostin A have been revealed to inhibit not only DNA binding of HIF-1 but also HIF-1α protein accumulation in MCF-7 cells. Furthermore, the thiosulfinate analogue and triostin A exhibited a hypoxia-selective cytotoxicity on MCF-7 cells. The improved solution-phase synthetic procedure described herein will contribute to the development of diverse bicyclic depsipeptide drug candidates with the potential to act as novel anti-cancer agents targeting hypoxic tumor microenvironments.

In the presence of a catalytic amount of Pd(OAc) 2 , various arylboronic acids underwent homocoupling in MeOH at ambient temperature under air to give rise to symmetrical biaryls. The homocoupling of arylboronic acids was also carried out using polyurea-encapsulated Pd(OAc) 2 as a recyclable catalyst.