A sulfoximine-based inhibitor of human asparagine synthetase kills l-asparaginase-resistant leukemia cells.

An adenylated sulfoximine transition-state analogue 1, which inhibits human asparagine synthetase (hASNS) with nanomolar potency, has been reported to suppress the proliferation of an l-asparagine amidohydrolase (ASNase)-resistant MOLT-4 leukemia cell line (MOLT-4R) when l-asparagine is depleted in the medium. We now report the synthesis and biological activity of two new sulfoximine analogues of 1 that have been studied as part of systematic efforts to identify compounds with improved cell permeability and/or metabolic stability. One of these new analogues, an amino sulfoximine 5 having no net charge at cellular pH, is a better hASNS inhibitor (K(I)(∗)=8nM) than 1 and suppresses proliferation of MOLT-4R cells at 10-fold lower concentration (IC(50)=0.1mM). More importantly, and in contrast to the lead compound 1, the presence of sulfoximine 5 at concentrations above 0.25mM causes the death of MOLT-4R cells even when ASNase is absent in the culture medium. The amino sulfoximine 5 exhibits different dose-response behavior when incubated with an ASNase-sensitive MOLT-4 cell line (MOLT-4S), supporting the hypothesis that sulfoximine 5 exerts its effect by inhibiting hASNS in the cell. Our work provides further evidence for the idea that hASNS represents a chemotherapeutic target for the treatment of leukemia, and perhaps other cancers, including those of the prostate

Recyclable Organocatalysts in Asymmetric Synthesis

Chiral organocatalysts are extensively in demand over the past 30 years for the synthesis of asymmetric compounds with remarkable stereoselectivities in high yields. In addition to these great facilities, they are eco-friendly, non-toxic, highly stable, and inexpensive structures so that a tremendous amount of studies has been developing. Besides, recyclable organocatalyst studies are of great interest to develop their environmental-friendly feature lately. Increasing the usage of these catalysts by saving the asymmetric results could become the most desirable characteristic in near future. This survey summarizes the following studies that have been done so far to enlight this subject and our headlights cover-up silica supported organocatalysts, polymer supported organocatalysts, magnetic nanoparticle supported organocatalysts, gold nanoparticle supported organocatalysts, ionic liquids organocatalysts and fluorous supported organocatalysts

Cystathionine is a novel substrate of cystine/glutamate transporter: Implications for immune function.

The cystine/glutamate transporter, designated as system xc-, is important for maintaining intracellular glutathione levels and extracellular redox balance. The substrate-specific component of system xc-, xCT, is strongly induced by various stimuli, including oxidative stress, whereas it is constitutively expressed only in specific brain regions and immune tissues such as thymus and spleen. While cystine and glutamate are the well-established substrates of system xc- and the knockout of xCT leads to alterations of extracellular redox balance, nothing is known about other potential substrates. We thus performed a comparative metabolite analysis of tissues from xCT-deficient and wild-type mice using capillary electrophoresis time-of-flight mass spectrometry. Although most of the analysed metabolites did not show significant alterations between xCT-deficient and wild-type mice, cystathionine emerged to be absent specifically in thymus and spleen of xCT-deficient mice. No expression of either cystathionine β-synthase or cystathionine γ-lyase was observed in thymus and spleen of mice. In embryonic fibroblasts derived from wild-type embryos, cystine uptake was significantly inhibited by cystathionine in a concentration-dependent manner. Wild-type cells showed an intracellular accumulation of cystathionine when incubated in cystathionine-containing buffer, which concomitantly stimulated an increased release of glutamate into the extracellular space. By contrast, none of these effects could be observed in xCT-deficient cells. Remarkably, unlike knockout cells, wild-type cells could be rescued from cystine deprivation-induced cell death by cystathionine supplementation. We thus conclude that cystathionine is a novel physiological substrate of system xc-, and that the accumulation of cystathionine in immune tissues is exclusively mediated by system xc-