Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate.

A flow photochemical reaction system for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence was developed, which utilizes in situ-generated 2-benzopyrylium intermediates as the photoredox catalyst and electrophilic substrates. The key 2-benzopyrylium intermediates were generated in the flow reaction system through the intramolecular cyclization of -carbonyl alkynylbenzene derivatives by the π-Lewis acidic metal catalyst AgNTf and the subsequent proto-demetalation with trifluoroacetic acid. The 2-benzopyrylium intermediates underwent further photoreactions with benzyltrimethylsilane derivatives as the donor molecule in the flow photoreactor to provide 1-isochromene derivatives in higher yields in most cases than the batch reaction system.

Consecutive π-Lewis acidic metal-catalysed cyclisation/photochemical radical addition promoted by generated 2-benzopyrylium as the photoredox catalyst.

A π-Lewis acidic metal-catalysed cyclisation/photochemical radical addition sequence was developed, which utilises generated 2-benzopyrylium cation intermediates as photoredox catalysts and electrophilic substrates to form 1-isochromene derivatives in good yields in most cases. The key 2-benzopyrylium intermediates were generated through the activation of the alkyne moiety of -carbonyl alkynylbenzene derivatives by such π-Lewis acidic metal catalysts as AgNTf and Cu(NTf), and the subsequent intramolecular cyclisation and proto-demetalation using trifluoroacetic acid. Further photo-excitation of the 2-benzopyrylium intermediates facilitated single-electron transfer from a benzyltrimethylsilane derivative as a donor molecule to promote the radical addition of arylmethyl radicals to the 2-benzopyrylium intermediates.

Application of linear and machine learning models to genomic prediction of fatty acid composition in Japanese Black cattle.

We collected 3180 records of oleic acid (C18:1) and monounsaturated fatty acid (MUFA) measured using gas chromatography (GC) and 6960 records of C18:1 and MUFA measured using near-infrared spectroscopy (NIRS) in intermuscular fat samples of Japanese Black cattle. We compared genomic prediction performance for four linear models (genomic best linear unbiased prediction [GBLUP], kinship-adjusted multiple loci [KAML], BayesC, and BayesLASSO) and five machine learning models (Gaussian kernel [GK], deep kernel [DK], random forest [RF], extreme gradient boost [XGB], and convolutional neural network [CNN]). For GC-based C18:1 and MUFA, KAML showed the highest accuracies, followed by BayesC, XGB, DK, GK, and BayesLASSO, with more than 6% gain of accuracy by KAML over GBLUP.

Inhibitory Effect of Pyra-Metho-Carnil on Cancer Spheroid Growth Through Decrease in Glycolysis-associated Molecules.

Background/aim: Pyra-Metho-Carnil (PMC) has been identified as a novel candidate compound for treating numerous malignancies; however, its mechanism of action remains unknown. In this study, we conducted RNA-sequencing (RNA-seq) analyses to elucidate the mechanism of PMC against human colorectal cancer cells harboring mutant KRAS (mtKRAS).

Materials And Methods: RNA-seq analyses of the HKe3-wild-type KRAS and HKe3-mtKRAS spheroids treated with DMSO or PMC for 6 days were performed.

α,β-Dehydroamino Acid Synthesis through Proline-Catalyzed Aldol Condensation with a Glycine Schiff Base.

A general protocol for the synthesis of α,β-dehydroamino acids and their peptides was developed. Proline efficiently catalyzed an aldol condensation reaction of a glycine Schiff base with a variety of aldehydes. The hydroxy group on the benzophenone imine was crucial for high / selectivity and further transimination for protecting group-free α,β-dehydroamino esters.

Cancer Spheroid Proliferation Is Suppressed by a Novel Low-toxicity Compound, Pyra-Metho-Carnil, in a Context-independent Manner.

Background/aim: In a screen of compounds to selectively suppress the growth of cancer spheroids, which contained mutant (mt) KRAS, NPD10621 was discovered and associated derivatives were investigated.

Materials And Methods: Spheroid areas from HCT116-derived HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were treated with 12 NPD10621 derivatives and measured in three-dimensional floating (3DF) cultures. Several cancers were treated with NPD1018 (pyra-metho-carnil: PMC) in 3DF cultures.

Catalytic Dehydrogenative β-Alkylation of Amino Acid Schiff Bases with Hydrocarbon.

A synthetic method for the synthesis of a highly congested α,β-dehydroamino acid through the β-C-H bond activation of an amino acid Schiff base is described. Abundant hydrocarbon feedstock could be used as an alkylating reagent to afford an α,β-dehydroamino acid bearing a quaternary carbon at the γ-position with an exclusively ()-geometry. Notably, a tetrasubstituted olefin could be constructed from saturated starting materials.

Growth Suppression of Cancer Spheroids With Mutated KRAS by Low-toxicity Compounds from Natural Products.

Background/aim: Among compounds from natural products selectively suppressing the growth of cancer spheroids, which have mutant (mt) KRAS, NP910 was selected and its derivatives explored.

Materials And Methods: The area of HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in three-dimensional floating (3DF) cultures treated with 18 NP910 derivatives. The 50% cell growth inhibition (GI50) was determined by long-term 3DF (LT3DF) culture and nude mice assay.

Development of Catalytic Reactions for Precise Control of Chemoselectivity.

Catalytic chemoselective reactions of innately less reactive functionalities over more reactive functionalities are described. A cooperative catalyst comprising a soft Lewis acid/hard Brønsted base enabled chemoselective activation of a hydroxyl group over an amino group, allowing for nucleophilic addition to electron-deficient olefins. The reaction could be applicable for a variety of amino alcohols, including pharmaceuticals, without requiring a tedious protection-deprotection process.

Union of the European Phoniatricians' position statement on the exit strategy of phoniatric and laryngological services: staying safe and getting back to normal after the peak of coronavirus disease 2019 (issued on 25th May 2020).

Background: The following position statement from the Union of the European Phoniatricians, updated on 25th May 2020 (superseding the previous statement issued on 21st April 2020), contains a series of recommendations for phoniatricians and ENT surgeons who provide and/or run voice, swallowing, speech and language, or paediatric audiology services.

Objectives: This material specifically aims to inform clinical practices in countries where clinics and operating theatres are reopening for elective work. It endeavours to present a current European view in relation to common procedures, many of which fall under the aegis of aerosol generating procedures.

Catalytic Aerobic Cross-Dehydrogenative Coupling of Azlactones en Route to α,α-Disubstituted α-Amino Acids.

We developed a catalytic aerobic method to synthesize α,α-disubstituted α-amino acids through cross-dehydrogenative coupling of azlactones. Combining an iron catalyst with a bisoxazolidine ligand resulted in high catalytic performance, and cross-coupling with an indole proceeded smoothly under aerobic conditions. A wide variety of α-aryl and aliphatic amino acid derived azlactones were applied to the present catalysis.

Amino Acid Schiff Base Bearing Benzophenone Imine As a Platform for Highly Congested Unnatural α-Amino Acid Synthesis.

Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function of peptides. We developed a new mode for catalytic activation of amino acid Schiff bases, serving as a platform for highly congested unnatural α-amino acid synthesis. The redox active copper catalyst enabled efficient cross-coupling to construct contiguous tetrasubstituted carbon centers.

Chemoselective Catalytic α-Oxidation of Carboxylic Acids: Iron/Alkali Metal Cooperative Redox Active Catalysis.

We developed a chemoselective catalytic activation of carboxylic acid for a 1e radical process. α-Oxidation of a variety of carboxylic acids, which preferentially undergo undesired decarboxylation under radical conditions, proceeded efficiently under the optimized conditions. Chemoselective enolization of carboxylic acid was also achieved even in the presence of more acidic carbonyls.

Growth Suppression of Human Colorectal Cancer Cells with Mutated by 3-Deaza-cytarabine in 3D Floating Culture.

Background/aim: During screening for compounds that selectively suppress growth of human colorectal cancer (CRC) spheroids with mutant (mt) KRAS, the uridine analogue, 5-bromouridine (BrUrd) was identified and its derivatives were explored.

Materials And Methods: DNA incorporation in two-dimensional (2D) and three-dimensional floating (3DF) cultures was examined with the uridine analogue, 5-ethynyl-2'-deoxyuridine (EdU). The area of HKe3 CRC spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in 3DF culture with 11 BrUrd derivatives.

Strategy for Catalytic Chemoselective Cross-Enolate Coupling Reaction via a Transient Homocoupling Dimer.

A new strategy, a transient homocoupling dimer strategy, for direct catalytic oxidative cross-enolate coupling reactions is developed. Cross-enolate coupling products bearing a (contiguous) tetrasubstituted carbon center were obtained chemoselectively without the need for stoichiometric amounts of strong bases/metal oxidants, and thus, the present catalysis provides a general method for the synthesis of unnatural α,α-disubstituted amino acid motifs. The distinct transformation of azlactone and 2-acylimidazole units highlighted the synthetic utility of the present catalysis.

An Expeditious Route to trans-Configured Tetrahydrothiophenes Enabled by Fe(OTf) -Catalyzed [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes with Thionoesters.

A synthetic route to trans-configured tetrahydrothiophenes (THTs) through Fe(OTf) -promoted [3+2] cycloaddition of donor-acceptor cyclopropanes with thionoesters was developed. The cycloaddition proceeded in high yield with high diastereoselectivity, affording transient α-alkoxy THTs. Not only aromatic and aliphatic thionoesters, but also thionolactone were applicable to the present iron catalysis.

Catalytic Aerobic Chemoselective α-Oxidation of Acylpyrazoles en Route to α-Hydroxy Acid Derivatives.

Catalytic aerobic chemoselective α-oxidation of acylpyrazoles is described. Acylpyrazoles, carboxylic acid oxidation state substrates, were efficiently oxidized under aerobic conditions using TEMPO as an oxygenating agent. The mild catalytic conditions of the present catalysis were amenable to late-stage α-oxidation of various pharmaceutical agents and natural products, leading to previously unreported α-hydroxy acid derivatives in short steps.

Catalytic Chemoselective Conjugate Addition of Amino Alcohols to α,β-Unsaturated Ester: Hydroxy Group over Amino Group and Conjugate Addition over Transesterification.

A highly chemoselective conjugate addition of amino alcohols to α,β-unsaturated ester using a soft Lewis acid/hard Brønsted base cooperative catalyst was developed. This catalysis achieved chemoselective addition of a hydroxy group over an amino group. Moreover, soft metal alkoxide generation enabled chemoselective soft conjugate addition over hard transesterification.

Chemo- and Regioselective Direct Functional Group Installation through Catalytic Hydroxy Group Selective Conjugate Addition of Amino Alcohols to α,β-Unsaturated Sulfonyl Compounds.

A chemoselective functional group installation through catalytic hydroxy group selective conjugate addition of amino alcohols to a variety of functionalized α,β-unsaturated sulfonyl derivatives was developed. Azide group installation for click chemistry and facile fluorescent labeling onto the less reactive hydroxy group demonstrated the synthetic utility of the present chemoselective catalysis. Moreover, chemo- and regioselective reaction of an unprotected amino diol was achieved for the first time.

μ-Oxo-Dinuclear-Iron(III)-Catalyzed O-Selective Acylation of Aliphatic and Aromatic Amino Alcohols and Transesterification of Tertiary Alcohols.

A highly chemoselective and reactive μ-oxo-dinuclear iron(III) salen catalyst for transesterification was developed. The developed iron complex catalyzed acylation of aliphatic amino alcohols with nearly perfect O-selectivity, even when using activated esters, for which chemoselectivity is more difficult to control. In addition, O-selective transesterification of aromatic amino alcohols was achieved for the first time.

Direct Catalytic Chemoselective α-Amination of Acylpyrazoles: A Concise Route to Unnatural α-Amino Acid Derivatives.

A direct copper-catalyzed highly chemoselective α-amination is described. Acylpyrazole proved to be a highly efficient enolate precursor of a carboxylic acid oxidation state substrate, while preactivation by a stoichiometric amount of strong base has been used in catalytic α-aminations. The simultaneous activation of both coupling partners, enolization and metal nitrenoid formation, was crucial for obtaining the product, and wide functional group compatibility highlighted the mildness of the present catalysis.

Broad-range detection of arboviruses belonging to Simbu serogroup lineage 1 and specific detection of Akabane, Aino and Peaton viruses by newly developed multiple TaqMan assays.

TaqMan assays were developed for the broad-range detection of arboviruses belonging to Simbu serogroup lineage 1 in the genus Orthobunyavirus and also for the specific detection of three viruses in the lineage, Akabane, Aino and Peaton viruses (AKAV, AINOV and PEAV, respectively). A primer and probe set was designed for the broad-range detection of Simbu serogroup lineage 1 (Pan-Simbu1 set) mainly targeting AKAV, AINOV, PEAV, Sathuperi and Shamonda viruses (SATV and SHAV), and the forward and reverse primers of the Pan-Simbu1 set were also used for the specific detection of AKAV with another probe (AKAV-specific set). In addition, two more primer and probe sets were designed for AINOV- and PEAV-specific detection, respectively (AINOV- and PEAV-specific sets).

Oxetanyl peptides: novel peptidomimetic modules for medicinal chemistry.

The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics.

Chemoselective catalytic conjugate addition of alcohols over amines.

A highly chemoselective conjugate addition of alcohols in the presence of amines is described. The cooperative nature of the catalyst enabled chemoselective activation of alcohols over amines, allowing the conjugate addition to soft Lewis basic α,β-unsaturated nitriles. Divergent transformation of the nitrile functionality highlights the utility of the present catalysis.

Direct catalytic asymmetric alkynylation of ketoimines.

An efficient protocol for direct catalytic alkynylation of ketoimines is described. The simultaneous activation of a soft Lewis basic terminal alkyne and a ketoimine bearing a thiophosphinoyl group by soft Lewis acid Cu(I) is crucial for high conversion. The reaction can be rendered asymmetric with a chiral bisphosphine ligand (S,S)-Ph-BPE.