Synthesis of N-Alkenylated Heterocycles via T3P-Promoted Condensation with Ketones.

Herein, we describe a convenient protocol for the synthesis of N-alkenylated heterocycles using abundant ketone electrophiles and T3P as a water scavenger under microwave irradiation. The method can be applied to a diverse range of NH-heterocycles and ketones with good to excellent yields (up to 94%). This procedure is particularly attractive, as it is metal- and base-free, tolerates a variety of functional groups, and offers ease of product purification. The utility of the protocol was exemplified by synthesizing pharmaceutically relevant scaffolds containing the N-alkenyl motif and was further extended to a one-pot reductive amination sequence.

Acyl Amidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and 11C Labeling.

A protocol for the carbonylative synthesis of acyl amidines from aryl halides, amidines, and carbon monoxide catalyzed by Pd(0) is reported herein. Notably, carbon monoxide is generated ex situ from a solid CO source, and several productive palladium ligands were identified with complementary benefits and substrate scope. Furthermore, sequential one-pot, two-step protocols for the synthesis of 1,2,4-triazoles and 1,2,4-oxadiazoles via acyl amidine intermediates are reported. In addition, this approach was extended to isotopic labeling using [11C]carbon monoxide to allow, for the first time, synthesis of 11C-labeled acyl amidines as well as a 11C-labeled 1,2,4-oxadiazole.

Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging.

We present a mass spectrometry imaging (MSI) approach for the comprehensive mapping of neurotransmitter networks in specific brain regions. Our fluoromethylpyridinium-based reactive matrices facilitate the covalent charge-tagging of molecules containing phenolic hydroxyl and/or primary or secondary amine groups, including dopaminergic and serotonergic neurotransmitters and their associated metabolites. These matrices improved the matrix-assisted laser desorption/ionization (MALDI)-MSI detection limit toward low-abundance neurotransmitters and facilitated the simultaneous imaging of neurotransmitters in fine structures of the brain at a lateral resolution of 10 µm. We demonstrate strategies for the identification of unknown molecular species using the innate chemoselectivity of the reactive matrices and the unique isotopic pattern of a brominated reactive matrix. We illustrate the capabilities of the developed method on Parkinsonian brain samples from human post-mortem tissue and animal models. The direct imaging of neurotransmitter systems provides a method for exploring how various neurological diseases affect specific brain regions through neurotransmitter modulation.

The Wittig bioconjugation of maleimide derived, water soluble phosphonium ylides to aldehyde-tagged proteins.

Herein we disclose the transformation of maleimides into water-soluble tris(2-carboxyethyl)phosphonium ylides and their subsequent application in the bioconjugation of protein- and peptide-linked aldehydes. The new entry into Wittig bioconjugate chemistry proceeds under mild conditions and relies on highly water soluble reagents, which are likely already part of most biochemists' inventory.

Regio- and Stereoselective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via an Intramolecular Mizoroki-Heck Reaction.

The palladium(0)-catalyzed intramolecular annulation of 12 1,3-disubstituted cyclopentenes, derived from (+)-vince lactam, resulted in 5-exo cyclizations which furnished a series of 2,5-dimethyl-1-((3R,4'S)-2H-spiro[benzofuran-3,1'-cyclopentan]-2'-en-4'-yl)-1H-pyrroles in excellent diastereoselectivities and useful isolated yields. The double bond migration process that followed the arylpalladium insertion was controlled by a fine-tuning of the reaction system, which provided regioselectivities of up to 98:2. The selective Mizoroki-Heck reaction was used as the key transformation for preparing two new spirocyclic monoprotected amino acids as single stereoisomers.

Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylsulfonamides via Regioselective Acylation.

N-Acylsulfonamides represent an important bioisostere of carboxylic acids that allow for greater molecular elaboration and enhanced hydrogen bonding capabilities. Herein, we present a mild and convenient palladium(0)-catalyzed synthesis of N-acylsulfonamides via the carbonylative coupling of sulfonyl azides and electron-rich heterocycles. The reaction proceeds via in situ generation of a sulfonyl isocyanate followed by regioselective acylation of an indole or pyrrole nucleophile. This approach has been used to synthesize 34 indole- and pyrrole-substituted N-acylsulfonamides in yields of up to 95%. Importantly, this process is ligand-free and compatible with an ex situ solid CO source and requires only slightly elevated temperatures, making it a highly attractive method for the preparation of this important class of compounds. This study further investigated the possibility of labeling N-acylsulfonamides with carbon-11 to facilitate biological evaluation and in vivo studies with positron emission tomography.

Synthesis of N-Sulfonyl Amidines and Acyl Sulfonyl Ureas from Sulfonyl Azides, Carbon Monoxide, and Amides.

A Pd-catalyzed and ligand-free carbonylation/cycloaddition/decarboxylation cascade synthesis of sulfonyl amidines from sulfonyl azides and substituted amides at low CO pressure is reported. The reaction proceeds via an initial Pd-catalyzed carbonylative generation of sulfonyl isocyanates from sulfonyl azides, followed by a [2 + 2] cycloaddition with amides and subsequent decarboxylation, which liberates the desired sulfonyl amidines, generating N2 and CO2 as the only reaction byproducts. Using this simple protocol, a diverse range of sulfonyl amidines was obtained in moderate to excellent yields. In addition, the reaction can also be directed through a more conventional amidocarbonylation pathway by employing N-monosubstituted amide nucleophiles to afford acyl sulfonyl ureas in good yields.

Palladium(0)-Catalyzed Carbonylative One-Pot Synthesis of N-Acylguanidines.

A convenient synthetic strategy toward N-acylguanidines via a sequential one-pot multicomponent carbonylation/amination reaction has been developed. The compounds were readily obtained via an N-cyanobenzamide intermediate formed from the Pd(0)-catalyzed carbonylative coupling of cyanamide and aryl iodides or bromides. Subsequent amination with a large variety of amines provided the final N-acylguanidines, with the overall formation of one C-C and two C-N bonds, in moderate to excellent yields. The substrate scope was found to be wide and the methodology was used to produce over 50 compounds, including 29 novel molecules. Furthermore, three separate nitrogen-containing heterocycles were prepared from the N-acylguanidines synthesized using the developed multicomponent, carbonylative method.

Synthesis and in vitro evaluation of 5-substituted benzovesamicol analogs containing N-substituted amides as potential positron emission tomography tracers for the vesicular acetylcholine transporter.

Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (±)-7i and (±)-7l had the highest affinities for VAChT. Compound (±)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the σ1 and σ2 receptors. Enantiomeric resolution gave (+)-7i and (-)-7i, and the eutomer showed seven times better affinity. Although racemate (±)-7i was initially promising, the affinity of (-)-7i for VAChT was not better than 56.7nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [11C]-(±)-7i shows that (-)-7i can serve as a scaffold for future optimizations to provide improved 11C-labelled VAChT PET tracers.

Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation.

Positron emission tomography is an imaging technique with applications in clinical settings as well as in basic research for the study of biological processes. A PET tracer, a biologically active molecule where a positron-emitting radioisotope such as carbon-11 has been incorporated, is used for the studies. Development of robust methods for incorporation of the radioisotope is therefore of the utmost importance. The urea functional group is present in many biologically active compounds and is thus an attractive target for incorporation of carbon-11 in the form of [11C]carbon monoxide. Starting with amines and [11C]carbon monoxide, both symmetrical and unsymmetrical 11C-labelled ureas were synthesised via a palladium(II)-mediated oxidative carbonylation and obtained in decay-corrected radiochemical yields up to 65%. The added advantage of using [11C]carbon monoxide was shown by the molar activity obtained for an inhibitor of soluble epoxide hydrolase (247 GBq/µmol-319 GBq/µmol). DFT calculations were found to support a reaction mechanism proceeding through an 11C-labelled isocyanate intermediate.

Mild and Low-Pressure fac-Ir(ppy)3 -Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible-Light Photoredox Catalysis.

A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)3 -catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)3 , amines, reductants, and CO gas (released ex situ from Mo(CO)6 ), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.

Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-Iodoanilines and Cyanamide.

Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin-4(3H)-ones and N1-substituted 2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization process. The reaction proceeds via carbonylative coupling of readily available ortho-iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide intermediate. The products were easily isolated by precipitation in moderate to excellent yields for a wide range of substrates, making this a highly attractive method for the synthesis of 2-aminoquinazolinones.

Sulfonyl Azides as Precursors in Ligand-Free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides.

An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a palladium-catalyzed carbonylation protocol has been developed. Using a two-chamber system, sulfonyl azides, PdCl2, and CO gas, released ex situ from Mo(CO)6, were assembled to generate sulfonyl isocyanates in situ, and alcohols and aryl amines were exploited as nucleophiles to afford a broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also developed.

Synthesis of 4-quinolones via a carbonylative Sonogashira cross-coupling using molybdenum hexacarbonyl as a CO source.

A palladium-catalyzed CO gas-free carbonylative Sonogashira/cyclization sequence for the preparation of functionalized 4-quinolones from 2-iodoanilines and alkynes via two different protocols is described. The first method (A) yields the cyclized products after only 20 min of microwave (MW) heating at 120 °C. The second method (B) is a gas-free one-pot two-step sequence which runs at room temperature, allowing the use of sensitive substituents (e.g., nitro and bromide groups). For both protocols, molybdenum hexacarbonyl was used as a solid source of CO.

A microwave-assisted multicomponent synthesis of substituted 3,4-dihydroquinazolinones.

A microwave-assisted, multicomponent protocol for the synthesis of substituted 3,4-dihydroquinazolinones via a novel cascade imine/cyclization/aza-Henry reaction sequence is reported. Starting from o-formyl carbamates, a series of structurally diverse 3,4-dihydroquinazolinones was synthesized via a cyclic iminium ion intermediate in moderate to excellent yields. Notably, the reaction is fast, flexible, simple to perform and tolerates a variety of functional groups.

1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity.

Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the Naphthaladyn™ series, with compounds 23 and 29 being the most active (IC50 of 19.1 ± 0.3 and 18.5 ± 1.7 µM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 µM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.

A novel p53 mutant found in iatrogenic urothelial cancers is dysfunctional and can be rescued by a second-site global suppressor mutation.

Exposure to herbal remedies containing the carcinogen aristolochic acid (AA) has been widespread in some regions of the world. Rare A→T TP53 mutations were recently discovered in AA-associated urothelial cancers. The near absence of these mutations among all other sequenced human tumors suggests that they could be biologically silent. There are no cell banks with established lines derived from human tumors with which to explore the influence of the novel mutants on p53 function and cellular behavior. To investigate their impact, we generated isogenic mutant clones by integrase-mediated cassette exchange at the p53 locus of platform (null) murine embryonic fibroblasts and kidney epithelial cells. Common tumor mutants (R248W, R273C) were compared with the AA-associated mutants N131Y, R249W, and Q104L. Assays of cell proliferation, migration, growth in soft agar, apoptosis, senescence, and gene expression revealed contrasting outcomes on cellular behavior following introduction of N131Y or Q104L. The N131Y mutant demonstrated a phenotype akin to common tumor mutants, whereas Q104L clone behavior resembled that of cells with wild-type p53. Wild-type p53 responses were restored in double-mutant cells harboring N131Y and N239Y, a second-site rescue mutation, suggesting that pharmaceutical reactivation of p53 function in tumors expressing N131Y could have therapeutic benefit. N131Y is likely to contribute directly to tumor phenotype and is a promising candidate biomarker of AA exposure and disease. Rare mutations thus do not necessarily point to sites where amino acid exchanges are phenotypically neutral. Encounter with mutagenic insults targeting cryptic sites can reveal specific signature hotspots.

Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and ¹5N NMR labeling experiments.

Imidazole-1-sulfonyl azide hydrogen sulfate is presented as an efficient reagent for the synthesis of sulfonyl azides from primary sulfonamides. The described method is experimentally simple and high-yielding and does not require the addition of Cu salts. Furthermore, (15)N NMR mechanistic studies show the reaction proceeds via a diazo transfer mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate provides a considerable advantage over existing diazo transfer reagents in terms of impact stability, cost, and ease of use.

Synthesis and evaluation of isoleucine derived angiotensin II AT(2) receptor ligands.

Sixteen new C-terminally modified analogues of 2, a previously described potent and selective AT2R ligand, were designed, synthesized and evaluated for their affinity to the AT2R receptor. The introduction of large, hydrophobic substituents was shown to be beneficial and the most active compound (17, Ki=8.5 µM) was over 12-times more potent than the lead compound 2.

Inhibition of glutamine synthetase: a potential drug target in Mycobacterium tuberculosis.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.