Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality and stress resistance while the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites and/or metabolic inhibitors by tracking resolution of double strand breaks (DSBs) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc’s effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in non-homologous end-joining (NHEJ) DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance and promote genomic instability.
A newly uncovered Brønsted acid-promoted [2+2+2] cycloaddition between siloxy alkynes and 1,2-diazines produces novel polycyclic compounds with high efficiency and excellent diastereoselectivity under exceedingly mild conditions. A small-molecule library synthesized using this reaction yielded a novel chemotype, which inhibited glycolytic ATP production by blocking glucose uptake in CHO-K1 cells.
The synthesis of new nitrogen-containing heterocycles plays a pivotal role in chemical biology and medicinal chemistry, as reflected by their many applications in the development of pharmacological probes and drugs. [1] Despite notable progress, there is a significant need for the identification of new nitrogen heterocycles which target previously unexplored regions of biogenic chemical space. Among the many possible synthetic strategies to such compounds, cycloadditions involving C-N multiple bonds are particularly attractive as they generate complex cyclic products by simultaneous formation of multiple bonds starting from readily available precursors. [2] Herein, we describe the discovery and development of a formal [2+2+2] cycloaddition of siloxy alkynes with phthalazines, a process that had not been previously described for either 1,2-diazines or electron-rich alkynes. [3][4][5][6][7] This effort has not only afforded heterocyclic products with a unique pentacyclic ring system but has also enabled the identification of a novel chemotype that inhibits glycolytic ATP production by direct blockage of glucose uptake in CHO-K1 cells. As a result of the prevalence of the Warburg effect in many human cancers, such compounds may prove useful in the development of new therapeutics which target reprogrammed energy metabolism of rapidly proliferating cells. [8] Our study began by examining the reaction of phthalazine (1) with the siloxy alkyne 2 in the presence of common Brønsted acids. While no reaction between 1 and 2 was observed in the absence of such additives, even at elevated temperatures, we found that addition of simple pyridinium salts promoted the formation of a new pentacyclic product (3; Scheme 1).After examining a range of mono-and bis(pyridinium) salts in various solvents, we determined the optimum protocol to entail the use of a stoichiometric amount of pyridinium trifluoromethanesulfonimide in CH 2 Cl 2 at room temperature, thus producing the lactam 3 as a single diastereomer in 77 % yield. While most of the known [2+2+2] cycloadditions typically require the presence of a transition-metal catalyst, [9] the present method promotes the condensation under remarkably mild reaction conditions, using only a simple, weak Brønsted acid. The excellent diastereoselectivity of this transformation is also highly noteworthy. The atom connectivity within the reaction product was initially determined to be that in 3 and is based on extensive use of NMR spectroscopic methods. Ultimately, the structure was secured and the relative stereochemistry of the three newly created stereogenic centers was defined through X-ray crystallographic analysis (see below).Interestingly, while a range of substituted mono-and bis(pyridinium) trifluoromethanesulfonimides were found to be effective as reaction promoters, the use of only HNTf 2 , in the absence of pyridine, produced 3 with lower efficiency (48 % yield) and diminished diastereoselectivity (83:17). Furthermore, the use of either pyridinium chloride, pyridinium p-toluenesulfo...
<p>Small molecules used in this study.</p>
<p>The antioxidants failed to restore IRIF kinetics after irradiation in 1 g/L glucose media.</p>
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