Identification of the Highly Active, Species Cross-Reactive Complex I Inhibitor BAY-179.

Mitochondria are key regulators of energy supply and cell death. Generation of ATP within mitochondria occurs through oxidative phosphorylation (OXPHOS), a process which utilizes the four complexes (complex I-IV) of the electron transport chain and ATP synthase. Certain oncogenic mutations (e.g., LKB1 or mIDH) can further enhance the reliance of cancer cells on OXPHOS for their energetic requirements, rendering cells sensitive to complex I inhibition and highlighting the potential value of complex I as a therapeutic target. Herein, we describe the discovery of a potent, selective, and species cross-reactive complex I inhibitor. A high-throughput screen of the Bayer compound library followed by hit triaging and initial hit-to-lead activities led to a lead structure which was further optimized in a comprehensive lead optimization campaign. Focusing on balancing potency and metabolic stability, this program resulted in the identification of BAY-179, an excellent in vivo suitable tool with which to probe the biological relevance of complex I inhibition in cancer indications.

Functional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia-specific tumor cell death.

Owing to lagging or insufficient neo-angiogenesis, hypoxia is a feature of most solid tumors. Hypoxic tumor regions contribute to resistance against antiproliferative chemotherapeutics, radiotherapy and immunotherapy. Targeting cells in hypoxic tumor areas is therefore an important strategy for cancer treatment. Most approaches for targeting hypoxic cells focus on the inhibition of hypoxia adaption pathways but only a limited number of compounds with the potential to specifically target hypoxic tumor regions have been identified. By using tumor spheroids in hypoxic conditions as screening system, we identified a set of compounds, including the phenothiazine antipsychotic Fluphenazine, as hits with novel mode of action. Fluphenazine functionally inhibits acid sphingomyelinase and causes cellular sphingomyelin accumulation, which induces cancer cell death specifically in hypoxic tumor spheroids. Moreover, we found that functional inhibition of acid sphingomyelinase leads to overactivation of hypoxia stress-response pathways and that hypoxia-specific cell death is mediated by the stress-responsive transcription factor ATF4. Taken together, the here presented data suggest a novel, yet unexplored mechanism in which induction of sphingolipid stress leads to the overactivation of hypoxia stress-response pathways and thereby promotes their pro-apoptotic tumor-suppressor functions to specifically kill cells in hypoxic tumor areas.

α-Arylation and Ring Expansion of Annulated Cyclobutanones: Stereoselective Synthesis of Functionalized Tetralones.

α-Arylcyclobutanones display unique reactivity that makes them valuable synthetic intermediates and target molecules. We describe the preparation of α-aryl- and α-heteroarylcyclobutanones through a direct α-arylation reaction. Problematic fragmentations are avoided by the use of LiOt Bu, which promotes a rapid but reversible self-aldol reaction that slowly releases the enolate required for α-arylation. We also demonstrate the ring expansion of α-arylcyclobutanones, a process that is highlighted in the stereoselective synthesis of 1-methoxy coniothyrinone D.

Efficient Routes to a Diverse Array of Amino Alcohol-Derived Chiral Fragments.

Efficient syntheses of chiral fragments derived from chiral amino alcohols are described. Several unique scaffolds were readily accessed in 1-5 synthetic steps leading to 45 chiral fragments, including oxazolidinones, morpholinones, lactams, and sultams. These fragments have molecular weights ranging from 100 to 255 Da and are soluble in water (0.085 to >15 mM).

Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.

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.

Ruthenium-catalyzed hydrohydroxyalkylation of acrylates with diols and α-hydroxycarbonyl compounds to form spiro- and α-methylene-γ-butyrolactones.

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 reactions 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 was probed using para-substituted 1-phenyl-1,2-propanediols 1g, 1m, and 1n and density functional theory calculations.

(S)-2-pentyl (R)-3-hydroxyhexanoate, a banana volatile and its olfactory recognition by the common fruit fly, Drosophila melanogaster.

The volatile organic compounds emitted from ripening bananas that elicit an antennal response from the common fruit fly, Drosophila melanogaster, were analyzed by a combination of gas chromatographic-electroantennographic detection, mass spectrometry, and (1)H NMR spectroscopy. These analyses revealed that the headspace of ripening bananas contains a number of EAD-active components including the new ester (S)-2-pentyl (R)-3-hydroxyhexanoate, the structural assignment of which was confirmed by chemical synthesis.

Inverse temperature dependence in the diastereoselective addition of Grignard reagents to a tetrahydrofurfural.

A remarkable example of inverse-temperature-dependent diastereoselectivity was uncovered while investigating the addition of Grignard reagents to a 3-hydroxytetrahydrofurfural. The free hydroxyl group in the tetrahydrofurfural was found to play a key role in these processes, a result corroborated through a series of DFT calculations that also highlighted an entropic preference for the formation of one diastereomer.

Development of a concise and general enantioselective approach to 2,5-disubstituted-3-hydroxytetrahydrofurans.

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.

A practical synthesis of alpha-aryl methyl ketones via a transition-metal-free Meerwein arylation.

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.