Protein
lysine methyltransferases have recently emerged as a new target class
for the development of inhibitors that modulate gene transcription
or signaling pathways. SET and MYND domain containing protein 2 (SMYD2)
is a catalytic SET domain containing methyltransferase reported to
monomethylate lysine residues on histone and nonhistone proteins.
Although several studies have uncovered an important role of SMYD2
in promoting cancer by protein methylation, the biology of SMYD2 is
far from being fully understood. Utilization of highly potent and
selective chemical probes for target validation has emerged as a concept
which circumvents possible limitations of knockdown experiments and,
in particular, could result in an improved exploration of drug targets
with a complex underlying biology. Here, we report the development
of a potent, selective, and cell-active, substrate-competitive inhibitor
of SMYD2, which is the first reported inhibitor suitable for in vivo
target validation studies in rodents.
We report herein a simple, scalable, transition-metal-free approach to the synthesis of alpha-aryl methyl ketones from diazonium tetrafluoroborate salts under mild conditions. This methodology uses easily accessible and nontoxic starting material and was applied to the multi-kilogram-scale preparation of 1-(3-bromo-4-methylphenyl)propan-2-one.
Under the conditions of ruthenium(0) catalyzed hydrohydroxyalkylation, vicinal diols 1a–1l and methyl acrylate 2a are converted to the corresponding lactones 3a–3l in good to excellent yield. The reaction of methyl acrylate 2a with hydrobenzoin 1f, benzoin didehydro-1f, and benzil tetradehydro-1f form the same lactone 3f product, demonstrating that this process may be deployed in a redox level-independent manner. A variety of substituted acrylic esters 2a–2h participate in spirolactone formation, as illustrated in the conversion of N-benzyl-3-hydroxyoxindole 1o to cycloadducts 4a–4h. Hydrohydroxyalkylation of hydroxyl-substituted methacrylate 2i with diols 1b, 1f, 1j and 1l forms α-exo-methylene-γ-butyrolactones 5b, 5f, 5j and 5l in moderate to good yield. A catalytic cycle involving 1,2-dicarbonyl-acrylate oxidative coupling to form oxaruthenacyclic intermediates is postulated. A catalytically competent mononuclear ruthenium(II) complex was characterized by single crystal X-ray diffraction. The influence of electronic effects on regioselectivity in reactions of nonsymmetric diols were probed using para-substituted 1-phenyl-1,2-propanediols 1g, 1m and 1n and density functional theory (DFT) calculations.
Concise syntheses of 2,5-disubstituted-3-hydroxytetrahydrofurans have been developed that provide access to each configurational isomer of this scaffold from a single aldol adduct. Application of these methods to the rapid preparation of (6S,7S,9S,10S)- and (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol, two structurally related marine epoxylipids, is reported.
The direct approach: Ruthenium(0)‐catalyzed hydrohydroxyalkylation of α‐olefins and styrenes with 3‐hydroxy‐2‐oxindoles forms branched products of CC coupling with high levels of diastereocontrol. A mechanism involving diene–olefin oxidative coupling and a subsequent carboxylic acid co‐catalyzed transfer hydrogenolysis of the resulting oxaruthenacycle intermediate is postulated.
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