Cancer cells are able to survive in difficult conditions, reprogramming their metabolism according to their requirements. Under hypoxic conditions they shift from oxidative phosphorylation to aerobic glycolysis, a behavior known as Warburg effect. In the last years, glycolytic enzymes have been identified as potential targets for alternative anticancer therapies. Recently, phosphoglycerate kinase 1 (PGK1), an ubiquitous enzyme expressed in all somatic cells that catalyzes the seventh step of glycolysis which consists of the reversible phosphotransfer reaction from 1,3-bisphosphoglycerate to ADP, has been discovered to be overexpressed in many cancer types. Moreover, several somatic variants of PGK1 have been identified in tumors. In this study we analyzed the effect of the single nucleotide variants found in cancer tissues on the PGK1 structure and function. Our results clearly show that the variants display a decreased catalytic efficiency and/or thermodynamic stability and an altered local tertiary structure, as shown by the solved X-ray structures. The changes in the catalytic properties and in the stability of the PGK1 variants, mainly due to the local changes evidenced by the X-ray structures, suggest also changes in the functional role of PGK to support the biosynthetic need of the growing and proliferating tumour cells.

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N-Bromosuccinimide-mediated electrophilic aromatic bromination of a series of anilines substituted with an electron-withdrawing group in the meta position was investigated. The regioselectivity of the reaction is markedly dependent on the polarity of the solvent and the bromination reaction can be tuned by appropriate selection of the reaction medium.Brominated aromatic compounds are of considerable interest, both for their intrinsic properties (numerous biologically active molecules contain a brominated aromatic unit) and for their use as reactive intermediates in the synthesis of important drugs, because of their ability to undergo carbon-carbon and carbon-heteroatom bondformation reactions.Electrophilic aromatic bromination was probably one of the earliest reaction to be discovered and studied by organic chemists. 1 Its mechanism is generally regarded as starting from a p-complex B, 2 a pre-reactive intermediate that evolves into a s-complex C (the Wheland intermediate), the formation of which represents the rate-determining step of the process in most cases (Scheme 1). 3 N-Bromosuccinimide is a well-known reagent for electrophilic aromatic bromination. In 1979, Mitchell et al. 4 reported that N-bromosuccinimide in N,N-dimethylformamide is a mild and selective reagent for nuclear monobromination of reactive aromatic compounds. Since then, several regioselective methods have been developed that use N-bromosuccinimide alone 5 or in combination with a variety of additives, both for deactivated 6 and activated 7 ortho-and para-disubstituted substrates. Surprisingly neither the regioselectivity nor the solvent effect in the bromination of meta-substituted aromatics with Nbromosuccinimide has been extensively investigated. meta-Substituted anilines 1a-h (Scheme 2), all of which contain an electron-withdrawing group, seemed to be appropriate starting points for our study, the aim of which was to explain some unexpected results obtained in our laboratories during routine synthetic work on analogous substrates. Bromination of 1a-h by N-bromosuccinimide was studied in a panel of seven solvents. Scheme 2 X = (a) NO 2 ; (b) CF 3 ; (c) CN; (d) CO 2 Me; (e) COMe; (f) F; (g) Cl; (h) Br The polarity of the solvents examined ranged from low in the case of dioxane [dielectric constant (e) = 2.2] to high in the case of dimethyl sulfoxide (DMSO; e = 47.2). The results obtained (Table 1) confirm that the regioselectivity of the reaction is markedly dependent on the solvent.Plots of the molar fraction of isomers 3a, 3d, 3e, and 3f against e (Figure 1a; curves for 3c, 3d, 3g, and 3h are not reported for the sake of clarity) show an almost linear correlation until e reaches a value of around 20, where the curves reach a plateau. A similar trend is observed with solvent mixtures of tetrahydrofuran (e = 7.5) with increasing fractions of water (e = 80) (Figure 1b; curve for 3b). Regardless of the nature of X, bromination seems to be very selective in polar media (DMF, DMSO), where 3 is formed almost exclusively.

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