Potent Uncompetitive Inhibitors of Nicotinamide N-Methyltransferase (NNMT) as In Vivo Chemical Probes.

NNMT uses SAM as a cofactor to catalyze the methylation of nicotinamide, producing 1-methylnicotinamide. Recent studies have shown that NNMT upregulation in cancer-associated fibroblasts (CAFs) is required to maintain the CAF phenotype in high-grade serous carcinoma. These observations suggest that NNMT should be evaluated as a therapeutic target, especially in cancer. Although several small-molecule inhibitors of NNMT have been identified, there remains a need for highly potent and selective inhibitors with excellent in vivo activity and ADME properties that can be used as reliable chemical probes. We have identified azaindoline carboxamide 38 as a selective and potent NNMT inhibitor with favorable PK/PD and safety profiles as well as excellent oral bioavailability and pharmaceutical properties. Our mechanistic studies indicate that 38 binds uncompetitively with SAM but competitively with nicotinamide consistent with its binding in the nicotinamide binding site and likely forming a positive interaction with SAM.

Stereoselective deconjugation of macrocyclic α,ß-unsaturated esters by sequential amidation and olefin transposition: application to enantioselective phase-transfer catalysis.

The stereoselective synthesis of chiral macrocycles bearing two aliphatic amide functional groups is reported. After the amidation mediated by TBD, a guanidine derivative, the olefin transposition step is performed with a slight excess of t-BuOK. The products are afforded in moderate to good combined yields (up to 59%) and with an excellent syn diastereoselectivity (dr > 49 : 1). Introducing enantiopure α-branched substituents was possible and it resulted in mixtures of diastereomers, which could be tested as phase-transfer catalysts using the formation of a phenylalanine analog as a test reaction (up to 43% ee). A clear matched-mismatched situation was observed in the two diastereomeric series.

The inverted ketene synthon: a double umpolung approach to enantioselective ß2,3-amino amide synthesis.

A stereocontrolled synthesis of ß2,3-amino amides is reported. Innovation is encapsulated by the first use of nitroalkenes to achieve double umpolung in enantioselective ß-amino amide synthesis. Step economy is also fulfilled by the use of Umpolung Amide Synthesis (UmAS) in the second step, delivering the amide product without intermediacy of a carboxylic acid or activated derivative. Molybdenum oxide-mediated hydride reduction provides the anti-ß2,3-amino amide with high selectivity.

One-Step Synthesis of Diaza Macrocycles by Rh(II)-Catalyzed [3 + 6 + 3 + 6] Condensations of Morpholines and α-Diazo-ß-ketoesters.

Selective formation of oxonium ylides from morpholines and α-diazo-ß-ketoesters was achieved. This was applied to the high-concentration (0.5 M) dirhodium-catalyzed (0.1 mol %) [3 + 6 + 3 + 6] synthesis of 18-membered ring diaza macrocycles (46%-72%). Late-stage functionalization of these derivatives is demonstrated. Mechanistic evidence for a novel (undesired) diazo decomposition pathway is also reported.

Catalytic, Enantioselective Synthesis of Cyclic Carbamates from Dialkyl Amines by CO2-Capture: Discovery, Development, and Mechanism.

Cyclic carbamates are a common feature of small-molecule therapeutics, offering a constrained hydrogen bond acceptor that is both polar and sterically small. Methods for their preparation most often focus first on amino alcohol synthesis and then reaction with phosgene or its equivalent. This report describes an enantioselective synthesis of cyclic carbamates in which carbon dioxide engages an unsaturated basic amine, facilitated by a bifunctional organocatalyst designed to stabilize a carbamic acid intermediate while activating it toward subsequent enantioselective carbon-oxygen bond formation. Six-membered cyclic carbamates are prepared in good yield with high levels of enantioselection, as constrained 1,3-amino alcohols featuring a chiral tertiary alcohol carbon. Spectroscopic analysis (NMR, DOSY) of various substrate-reagent combinations provides insight into the dominant species under the reaction conditions. Two peculiar requirements were identified to achieve highest consistency: a "Goldilocks" amount of water and the use of a noncrystalline form of the ligand. These atypical features of the final protocol notwithstanding, a diverse range of products could be prepared. Their functionalizations illustrate the versatility of the carbamates as precursors to enantioenriched small molecules.

Efficient Synthesis of Ditopic Polyamide Receptors for Cooperative Ion Pair Recognition in Solution and Solid States.

Following a late-stage functionalization strategy, a series of heteroditopic cryptand receptors were prepared in three steps only from 1,4-dioxane. As evidenced by 1 H NMR spectroscopic and solid state analyses, these polyamide-crown ether conjugates present general ion pair binding capacity towards salts of monovalent cations and linear triatomic anions.

A Ratiometric Luminescent Switch Based on Platinum Complexes Tethered to a Crown-Ether Scaffold.

A ratiometric chemosensor for potassium is reported, based on phosphorescent dinuclear cyclometalated Pt(II) complexes featuring a cis-crown ether as the cation-recognition unit. The metal complexes are blue luminescent in a non-aggregated state but become strongly orange emissive when in a close physical proximity, as is the case when the macrocycle is in the folded state. Upon binding of the cation, unfolding occurs, resulting in a pronounced change in the emission properties (e.g. emission wavelength), which can be used for ratiometric sensing applications. The reversibility of the binding was confirmed by competitive titration experiments with unsubstituted 18-crown-6; the system shows supramolecular switching behavior.

Potassium ion-selective fluorescent and pH independent nanosensors based on functionalized polyether macrocycles.

We present here a new family of pH insensitive ion-selective optical sensors based on emulsified nanospheres containing densely functionalized 15-, 16-, 18- and 20-membered pyreneamide derivatives. These compounds were successfully synthesized by the reaction of α-diazo-ß-ketoesters with cyclic ethers of the desired size in the presence of dirhodium complexes followed by a stereo-selective tandem amidation-transposition process and characterized by 1H-NMR, 13C-NMR, IR, HR-ESI-MS, UV-VIS and fluorescence spectroscopy and potentiometry. Their unique structure consisting of a crown ether ring linked to pyrene moieties through amide groups exhibits on-off switchable behavior upon binding of specific cations and allows one to incorporate these chemosensors as fluorescent ionophores into ion-exchange nanospheres. The nanosphere matrix is composed of bis(2-ethylhexyl)sebacate (DOS), poly(ethylene glycol) (PEG), sodium tetrakis 3,5-bis(trifluoromethyl)phenyl borate and pyreneamide functionalized 18-crown-6 ether (18C6). These optode nanoparticles exhibit a strong affinity to the potassium cation over other metal ions up to the millimolar concentration range in an exhaustive detection mode. The logarithmic complex formation constant was determined using the segmented sandwich membrane method and was found to be 6.5 ± 0.3 (SD) in PVC membrane plasticized with NPOE and 5.3 ± 0.3 (SD) in DOS with a 1 : 1 complex stoichiometry. The nanosensors were characterized in broad range of pH from 4 to 10 and the same linear calibration curves were obtained in the concentration range from 10-7 M to 10-5 M and thus the pH dependent response was largely overcome. These nanosensors are sufficiently stable, simple to prepare, exhibit a rapid response and their nanoscale size makes them suitable for sensing purposes in samples of limited dimensions.

Remote stereoselective deconjugation of α,ß-unsaturated esters by simple amidation reactions.

The thermodynamically disfavored isomerization of α,ß-unsaturated esters to deconjugated ß,γ-unsaturated analogues occurs readily when coupled to an amidation. Within the framework of macrocyclic derivatives, it is shown that 15, 16, and 18 membered macrocycles react with tBuOK and anilines to generate, in one-pot, ß,γ-unsaturated amides (yields up to 88%). Importantly, single (chiral) diastereomers are isolated (d.r. > 49 : 1, 1H NMR) irrespective of the size and nature of the rings, showing an effective transmission of remote stereochemistry during the isomerization process. CSP-chromatographic resolution and absolute configuration determination by VCD are achieved.