The discovery of the dipeptide gamma-glutamyltaurine (gamma-GT; glutaurine, Litoralon) in the parathyroid in 1980 and later in the brain of mammals gave rise to studies on intrinsic and synthetic taurine peptides of this type. It was suggested that gamma-glutamyltransferase (GGT; gamma-glutamyltranspeptidase) in the brain is responsible for the in vivo formation of this unusual dipeptide. gamma-GT has been prepared by both synthetic and enzymatic methods. The chemical syntheses included the use of protecting groups and coupling methods. A wide spectrum of analytical and spectroscopic methods was used to confirm the structure of the synthetic compounds and to elucidate the position of the peptide bond. Enzymatic preparation of gamma-GT from taurine takes advantage of the selective transpeptidation action of GGT on L-glutamine, glutathione, gamma-glutamyl-p-nitroanilide or other glutamine donors. Although the functional roles of gamma-GT in the brain are only poorly understood, many of its established CNS effects have been reported in the last 25 years. Its effect on emotional arousal and its anti-conflict potencies are synergistic with the anxiolytic drug diazepam. gamma-GT exhibits anti-conflict potency, which is exerted by reducing aversion or phobia and/or the anxiety levels. gamma-GT also acts as endogenous modulator in excitatory aminoacidergic neurotransmission. It is suggested that such acidic peptides through N-methyl-D-aspartic acid receptors could be part of the neurochemical substrate underlying self-stimulation of the medial prefrontal cortex. Other gamma-GT effects in neural systems include: effects on the monoamine concentration in the brain; effects on aggressive behavior in the cat; effects on thyroid hormones in the rat; amelioration of electroshock-induced amnesia; potent and long-lasting antiepileptic action (on intra-amygdaloid injection); affect the glutamatergic system in schizophrenic disorders. Roles for gamma-GT in non-neural systems have also been reported, e.g., effects on the metamorphosis of amphibians; on plasma rennin regulation; on radiation protection; on uric acid levels; on human antibody-dependent cell-mediated cytotoxicity (ADCC) and many more.

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Summary Naphthoquinones, such as menadione, display lower toxicity than anthracyclins used in cancer chemotherapy. Novel anti‐leukaemic compounds comprised of chloro‐amino‐phenyl naphthoquinones with substitutions on the benzoic ring were developed. Structure–activity relationship studies indicated that the analogue with both methyl and amine substitutions (named TW‐92) was the most efficient in killing leukaemic cells. Treatment of U‐937 promonocytic cells with TW‐92 induced apoptotic or necrotic cell death, dependent on incubation and dose conditions. TW‐92 induced rapid phosphorylation of p38 mitogen‐activated protein kinase (p38MAPK) and of extracellular signal‐regulated protein kinases (ERK1/2). The generation of apoptosis was preceded by intracellular H2O2 accumulation accompanied by glutathione depletion, the former inhibited by di‐phenyl‐iodonium (DPI), an inhibitor of NADPH oxidase. TW‐92 induced swelling of isolated rat liver mitochondria, indicative of a direct effect on mitochondria. Apoptosis in intact cells was accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase activation. In addition, the level of Mcl‐1, an anti‐apoptotic regulatory protein, was down‐regulated, whereas the expression of the pro‐apoptotic BAX was elevated. Finally, TW‐92 exerted strong pro‐apoptotic and necrotic effects in primary acute myeloid leukaemia samples when given in submicromolar concentrations. Together, these findings demonstrate that TW‐92 may provide an effective anti‐leukaemic strategy.

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Quinones Q 0910Direct Nitration of 3-Arylamino-2-chloro-1,4-naphthoquinones. -The nitration of readily accessible 3-arylamino-2-chloro-1,4-naphthoquinones with mixtures of nitric acid and sulfuric acid is studied in connection with pharmaceutical investigations. -(WIN, T.; YERUSHALMI, S.; BITTNER*, S.; Synthesis 2005, 10, 1631-1634; Dep. Chem., Ben Gurion Univ. Negev, Beer-Sheva 84105, Israel; Eng.) -Mais 46-092