- Unveiling novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl)quinolines as GPCR ligands via PI3-kinase/PAR-1 antagonism and platelet aggregation valuations; development of a new class of anticancer drugs with thrombolytic effects
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In the present study, novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl) quinolines (4a-l) were recognized and evaluated as G-Protein Coupled Receptor (GPCR) ligands through molecular evaluations. Thrombin mediates adhesion of mast cell, a type of cell abundantly found in connective tissue and releasing histamine and other substances during inflammatory and allergic reactions, through phosphoinositol 3-kinase pathway. With this background, as preliminary, 4a-l are resolute to be potential leads, designated from their effective phosphoinositol 3-kinase (PI3-Kinase) inhibition potentials, best-docked scores, comparative ligand efficiency, and significant structural attributes evaluated by ab initio simulations. Since thrombin is one of the main reason for various cancer invasion in association with PI3Kinase, a thrombolytic potential of the compounds also analyzed. The experimental in vitro studies confirmed the significant enhancement as PI3Kinase inhibitors and appreciable enhancement in MTT assay of breast and skin cancer cell lines. Significantly, acetophenone substituent in the quinoline scaffold could be coherent to note the significant binding affinity to all the evaluated drug targets.
- Thangarasu,Thamarai Selvi,Manikandan
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Read Online
- The New Chemical Reporter 6-Alkynyl-6-deoxy-GlcNAc Reveals O-GlcNAc Modification of the Apoptotic Caspases That Can Block the Cleavage/Activation of Caspase-8
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O-GlcNAc modification (O-GlcNAcylation) is required for survival in mammalian cells. Genetic and biochemical experiments have found that increased modification inhibits apoptosis in tissues and cell culture and that lowering O-GlcNAcylation induces cell death. However, the molecular mechanisms by which O-GlcNAcylation might inhibit apoptosis are still being elucidated. Here, we first synthesize a new metabolic chemical reporter, 6-Alkynyl-6-deoxy-GlcNAc (6AlkGlcNAc), for the identification of O-GlcNAc-modified proteins. Subsequent characterization of 6AlkGlcNAc shows that this probe is selectively incorporated into O-GlcNAcylated proteins over cell-surface glycoproteins. Using this probe, we discover that the apoptotic caspases are O-GlcNAcylated, which we confirmed using other techniques, raising the possibility that the modification affects their biochemistry. We then demonstrate that changes in the global levels of O-GlcNAcylation result in a converse change in the kinetics of caspase-8 activation during apoptosis. Finally, we show that caspase-8 is modified at residues that can block its cleavage/activation. Our results provide the first evidence that the caspases may be directly affected by O-GlcNAcylation as a potential antiapoptotic mechanism.
- Chuh, Kelly N.,Batt, Anna R.,Zaro, Balyn W.,Darabedian, Narek,Marotta, Nicholas P.,Brennan, Caroline K.,Amirhekmat, Arya,Pratt, Matthew R.
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Read Online
- Self-organizing oligothiophene-nucleoside conjugates: Versatile synthesis via "Click"-chemistry
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A versatile synthesis of novel oligothiophene-nucleoside conjugates based on Cu(l)-catalyzed alkyne-azide cycloaddition ("click-reaction") has been developed. Complementary thymidine- and adenosine-functionalized quaterthiophenes form recognition-driven superstructures via hydrogen bonding and other competing intermolecular forces. Self-aggregated fibers up to 30 μm in length were characterized with atomic force microscopy.
- Jatsch, Anja,Kopyshev, Alexey,Mena-Osteritz, Elena,Baeuerle, Peter
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Read Online
- Guiding suprastructure chirality of an oligothiophene by a single amino Acid
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Within the present work, synthesis and properties of three stereoisomeric hybrid materials consisting of a π-conjugated oligothiophene backbone and a single amino acid (proline), which is attached by click chemistry, are described. The hybrids were in particular investigated regarding their self-assembling behavior in solution. From optical investigations, including circular dichroism spectroscopy, the formation of chiral suprastructures could be deduced and correlated with the stereochemistry of the proline residue. In addition, an elaborate theoretical model of the compounds' self-assembly into suprastructures was developed on the basis of the experimental findings.
- Schillinger, Eva-Kathrin,Kuemin, Michael,Digennaro, Angela,Mena-Osteritz, Elena,Schmid, Sylvia,Wennemers, Helma,Baeuerle, Peter
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Read Online
- Tuning Excited-State Properties of [2.2]Paracyclophane-Based Antennas to Ensure Efficient Sensitization of Lanthanide Ions or Singlet Oxygen Generation
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The multistep synthesis of original antennas incorporating substituted [2.2]paracyclophane (pCp) moieties in the π-conjugated skeleton is described. These antennas, functionalized with an electron donor alkoxy fragment (A1) or with a fused coumarin derivative (A2), are incorporated in a triazacyclonane macrocyclic ligand L1 or L2, respectively, for the design of Eu(III), Yb(III), and Gd(III) complexes. A combined photophysical/theoretical study reveals that A1 presents a charge transfer character via through-space paracyclophane conjugation, whereas A2 presents only local excited states centered on the coumarin-paracyclophane moiety, strongly favoring triplet state population via intersystem crossing. The resulting complexes EuL1 and YbL2 are fully emissive in red and near-infrared, respectively, whereas the GdL2 complex acts as a photosensitizer for the generation of singlet oxygen.
- Wu, Shiqi,Galán, Laura Abad,Roux, Margaux,Riobé, Fran?ois,Le Guennic, Boris,Guyot, Yannick,Le Bahers, Tangui,Micouin, Laurent,Maury, Olivier,Benedetti, Erica
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supporting information
p. 16194 - 16203
(2021/11/04)
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- Application of FSO2N3 in preparation of diazo reagent
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The invention discloses application of FSO2N3 in preparation of a diazo reagent. The application comprises the following step: in the presence of alkali, FSO2N3 and acetone dimethyl phosphate as shown in a formula 2 are subjected to a reaction as shown in the specification, and a Bestmann-Ohira and/or Seyferth-Gilbert reagent is obtained. According to the application, the Seyferth-Gilbert reagent and/or the Bestmann-Ohira reagent can be obtained at a high yield in half an hour, the two mixed reagents generated in the reaction do not need to be separated, and the one-pot method is directly applied to the synthesis of the terminal alkyne compound. And/or like.
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Paragraph 0103-0106
(2021/06/06)
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- Synthesis of the C1-C27 Fragment of Stambomycin D Validates Modular Polyketide Synthase-Based Stereochemical Assignments
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The stambomycins are a family of bioactive macrolides isolated from Streptomyces ambofaciens. Aside from two stereocenters installed through cytochrome P450 oxidations, their stereochemistry has been predicted by sequence analysis of the polyketide synthase. We report a synthesis of the C1-C27 fragment of stambomycin D, the spectroscopic data of which correlates well with that of the natural product, further validating predictive sequence analysis as a powerful tool for stereochemical assignment of complex polyketide natural products.
- Anderson, Edward A.,Bernasconi, Alice,Blanco, Araceli,Challis, Gregory L.,Chintalapudi, Venkaiah,Gudmundsson, Haraldur G.,Lim, Jieyan,Song, Lijiang,Tran, Minh
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supporting information
p. 7439 - 7444
(2021/10/01)
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- Ambruticins: tetrahydropyran ring formation and total synthesis
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The ambruticins are a family of polyketide natural products which exhibit potent antifungal activity. Gene knockout experiments are in accord with the proposal that the tetrahydropyran ring of the ambruticins is formedviathe AmbJ catalysed epoxidation of the unsaturated 3,5-dihydroxy acid, ambruticin J, followed by regioselective cyclisation to ambruticin F. Herein, a convergent approach to the total synthesis of ambruticin J is described as well as model studies involving epoxidation and cyclisations of unsaturated hydroxy esters to give tetrahydropyrans and tetrahydrofurans. The total synthesis involves preparation of three key fragments which were unitedviaa Suzuki-Miyaura cross-coupling and Julia-Kocienski olefination to generate the required carbon framework. Global deprotection to a triol and selective oxidation of the primary alcohol gave, after hydrolysis of the lactone, ambruticin J.
- Bowen, James I.,Crump, Matthew P.,Wang, Luoyi,Willis, Christine L.
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supporting information
p. 6210 - 6215
(2021/07/28)
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- Synthesis of chiral branched allylamines through dual photoredox/nickel catalysis
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Allylamines are versatile building blocks in the synthesis of various naturally occurring products and pharmaceuticals. In contrast to terminal allylamines, the methods of synthesis of their branched congeners with internal, stereodefined double bonds are less explored. This work describes a new approach for the preparation of allylaminesviacross-coupling of alkyl bromides with simple 3-bromoallylamines by merging the photoredox approach and Ni catalysis. The reaction proceeds under mild conditions, under blue light irradiation, and in the presence of an organic dye, 4CzIPN, as a photocatalyst. The scope of suitable reaction partners is broad, including alkyl bromides bearing reactive functionalities (e.g., esters, nitriles, aldehydes, ketones, epoxides) andN-protected allylamines, as well asN-allylated secondary and tertiary amines and heterocycles. The employment of non-racemic starting materials allows for rapid and easy construction of complex multifunctional allylamine derivatives without the loss of enantiomeric purity.
- Garbacz, Mateusz,Stecko, Sebastian
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supporting information
p. 8578 - 8585
(2021/10/20)
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- 1-CYANO-PYRROLIDINE DERIVATIVES AS DUB INHIBITORS
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The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 or ubiquitin specific peptidase 30 (USP30). The novel compounds have formula (I): (Formula (I)) or are pharmaceutically acceptable salts thereof, wherein: R1a, R1b, R1c, R1d, R1e and R1f each independently represent hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C4 cycloalkyl, or R1b and R1c together form an optionally substituted C3-C6 cycloalkyl ring, or R1d and R1e together form an optionally substituted C3-C6 cycloalkyl ring; R2 represents hydrogen or optionally substituted C1-C6 alkyl; A represents an optionally further substituted 5 to 10 membered monocyclic or bicyclic heteroaryl, heterocyclyl or aryl ring; L represents a covalent bond or linker; B represents an optionally substituted 3 to 10 membered monocyclic or bicyclic heterocyclyl, heteroaryl, cycloalkyl or aryl ring; and when -A-L-B is at position x attachment to A is via a carbon ring atom of A, and either: A cannot be triazolopyridazinyl, triazolopyridinyl, imidazotriazinyl, imidazopyrazinyl or pyrrolopyrimidinyl; or B cannot be substituted with phenoxyl; or B cannot be cyclopentyl when L is an oxygen atom.
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Paragraph 0635-0636; 0691-0692
(2020/11/30)
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- Structure-Elucidating Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone C §
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The (polyenoyl)tetramic acid militarinone C (1) heads a family of seven members. Before our work, the configuration of C-5 was unknown whereas the configurations of C-8′ and C-10′ were either (R,R) or (S,S). We synthesized the four stereoisomers of constitution 1, which conform with these insights. This included cross-coupling both enantiomers of the western building block (8) with both enantiomers of the eastern building block (9). The specific rotations of the resulting 1 isomers suggested that natural 1 is configured like the coupling partners (S)-8 and (R,R)-9. This conclusion was corroborated by degrading natural 1 to alcohol 35 and by proving its configurational identity with synthetic (R,R)-35.
- Brückner, Reinhard,Drescher, Christian,Hamburger, Matthias,Keller, Morris,Potterat, Olivier
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supporting information
(2020/03/30)
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- SYNTHETIC RETINOIDS FOR USE IN RAR ACTIVATION
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The present invention relates to compounds of formula I: in which A1-A7 and R1 to R5 are defined herein, for use in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). The invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In an aspect, the invention relates to a method of screening compounds for therapeutic potential in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). Aspects of the invention relate to novel compounds of formula I in which at least one of A1 to A3 is N or at least one of A4 is CR12 or A5 is CR13 in which R12/R13 is halogen.
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Page/Page column 22
(2020/09/27)
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- Synthesis and Biological Evaluation of a Library of AGE-Related Amino Acid Triazole Crosslinkers
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Three N-Boc-protected amino acids, l-serine, l-aspartic, and l-glutamic acid, were either converted into their methyl azidoalkanoates or various alkynes via Bestmann-Ohira strategy or via reaction with propargylamine and propargyl bromide, respectively. The Cu-catalyzed click reaction provided a library of amino acid based triazoles, which were further N-methylated to triazolium iodides or deprotected and precipitated as free amino acid triazole dihydrochlorides. The biological properties of all derivatives were investigated by cytotoxicity assay (against L929 mouse fibroblasts) and broth microdilution method (E. coli ΔTolC and S. aureus). First results reveal complete inactivity for triazolium iodides with cell viabilities and microbial growths nearly 100 %, indicating them as possible analogs of advanced glycation endproducts (AGEs).
- Agelidis, Nektarios,Altevogt, Luca,Baro, Angelika,Bilitewski, Ursula,Bugdayci, Bakiye,Icik, Esra,Jolly, Anthony,L?ffler, Paul,Laschat, Sabine
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supporting information
(2020/09/01)
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- Au-Cavitands: Size governed arene-alkyne cycloisomerization
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With an inwardly directed reactive center and a well-defined binding pocket, Au(I) functionalized resorcin[4]arene cavitands have been shown to catalyze molecular transformations. The reactivity profiles that emerge differ from other Au(I) catalysts. The added constraint of a binding pocket gives rise to the possibility that the substrates might have to fit into the resorcinarene pocket; our hypothesis is that substrates that match the available space have different reaction outcomes than those that do not. Herein we report on the intramolecular cyclization of alkyne-aromatic substrates with variable alkynes and aromatic composition. We see that scaffold size most drastically dictates reactivity, especially when the substrate's features are particularly designed. The results of these experiments add to the veritable goldmine of information about the selectivity in catalysis that cavitands offer.
- Rusali, Lisa E.,Schramm, Michael P.
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supporting information
(2020/09/15)
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- Asymmetric Synthesis and Chiroptical Properties of Enantiopure Helical Ferrocenes
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An enantiopure helical ferrocene (Rp)-5 with five ortho-condensed aromatic rings was synthesized using a PtCl2-catalyzed cycloisomerization of planar-chiral 2-ethynyl-1-(4-phenanthrenyl)ferrocene (Rp)-6f, prepared in 3 steps from known enantiopure sulfinyl ferrocenyl boronic acid (SS,Sp)-7, as the source of planar chirality. This pentacyclic helical ferrocene showed a very high optical rotation value and strong circular dichroism (CD) signals.
- Urbano, Antonio,Del Hoyo, Ana M.,Martínez-Carrión, Alicia,Carre?o, M. Carmen
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supporting information
p. 4623 - 4627
(2019/06/17)
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- Balancing Bulkiness in Gold(I) Phosphino-triazole Catalysis
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The syntheses of a series of 1-phenyl-5-phosphino 1,2,3-triazoles are disclosed, within which, the phosphorus atom (at the 5-position of a triazole) is appended by one, two or three triazole motifs, and the valency of the phosphorus(III) atom is completed by two, one or zero ancillary (phenyl or cyclohexyl) groups respectively. This series of phosphines was compared with tricyclohexylphosphine and triphenylphosphine to study the effect of increasing the number of triazoles appended to the central phosphorus atom from zero to three triazoles. Gold(I) chloride complexes of the synthesised ligands were prepared and analysed by techniques including single-crystal X-ray diffraction structure determination. Gold(I) complexes were also prepared from 1-(2,6-dimethoxy)-phenyl-5-dicyclohexyl-phosphino 1,2,3-triazole and 1-(2,6-dimethoxy)-phenyl-5-diphenyl-phosphino 1,2,3-triazole ligands. The crystal structures thus obtained were examined using the SambVca (2.0) web tool and percentage buried volumes determined. The effectiveness of these gold(I) chloride complexes to serve as precatalysts for alkyne hydration were assessed. Furthermore, the regioselectivity of hydration of but-1-yne-1,4-diyldibenzene was probed.
- Zhao, Yiming,Wakeling, Matthew G.,Meloni, Fernanda,Sum, Tze Jing,van Nguyen, Huy,Buckley, Benjamin R.,Davies, Paul W.,Fossey, John S.
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supporting information
p. 5540 - 5548
(2019/08/07)
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- One-Pot Conversion of Aldehydes and Aryl Halides to Disubstituted Alkynes via Tandem Seyferth-Gilbert Homologation/Copper-Free Sonogashira Coupling
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A practically convenient protocol has been developed to convert a mixture of an aldehyde, aryl halide, and the Bestmann-Ohira reagent into disubstituted acetylene via a successive addition of base (Cs2CO3) and a Pd(II) catalyst, allowing sufficient time after addition of each of these reagents for the tandem processes (Seyferth-Gilbert homologation and Sonogashira coupling) to occur. Notably, for the latter reaction, no copper catalyst was required.
- Sapegin, Alexander,Krasavin, Mikhail
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p. 8788 - 8795
(2019/07/03)
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- Synthesis and use of a cost-effective, aqueous soluble diazo transfer reagent – m-carboxybenzenesulfonyl azide
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Herein, we report the preparation and use of m-carboxybenzenesulfonyl azide as a diazo transfer reagent. This compound is an inexpensive and potentially scalable alternative to many of the diazo transfer reagents currently available, most of which have hazards associated with their use. Its usefulness and suitability as a diazo transfer reagent was assessed on the basis of cost, safety and its effectiveness in diazo transfer to a variety of different substrates.
- O'Mahony, Rosella M.,Broderick, Caoimhe M.,Lynch, Denis,Collins, Stuart G.,Maguire, Anita R.
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supporting information
p. 35 - 39
(2018/12/05)
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- Chlorobenzene-pyridine compounds and application thereof
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The invention relates to chlorobenzene-pyridine compounds and an application thereof. The compounds can be used for preparing a Smoothened protein inhibitor and a drug for resisting adenocarcinoma andesophagus cancer and have the structure in the general formula (I) shown in the description, wherein X is selected from the structure shown in the description, R1 is selected from H or the structureshown in the description, and R2 is selected from the structure shown in the description.
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Paragraph 0051; 0056; 0057; 0058
(2018/04/01)
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- m-aminophenylacetylene preparation method
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The invention discloses an m-aminophenylacetylene preparation method, which comprises: carrying out a reaction on dimethyl acetylmethylphosphonate and tosyl azide under a strong alkali condition to obtain dimethyl(1-diazo-2-oxopropyl)phosphonate; carrying out a reaction on the dimethyl(1-diazo-2-oxopropyl)phosphonate and m-nitrobenzaldehyde under an alkaline catalyst condition to obtain m-nitrophenylacetylene; and reducing the m-nitrophenylacetylene to obtain the m-aminophenylacetylene. According to the present invention, the easily-available raw material m-nitrobenzaldehyde is used so as to avoid the use of the expensive raw materials such as m-iodonitrobenzene, m-bromonitrobenzene or m-nitrophenylacetylene and reduce the production cost; and the synthesis method has advantages of simpleoperation, no requirement of high pressure equipment, no requirement of vacuum rectification, simple requirement on equipment, cost saving and low environment pollution, and is suitable for industrialproduction.
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Paragraph 0035-0038
(2018/10/11)
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- Convergent Synthesis of Kibdelone C
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The synthesis of kibdelone C, a polycyclic natural xanthone isolated from a soil actinomycete, was achieved through a convergent approach. A 6?€-electrocyclization was applied to construct the highly substituted dihydrophenanthrenol fragment (B-C-D ring). InBr3-promoted lactonization was employed to build the isocoumarin ring, which served as a common precursor for the formation of isoquinolinone ring (A-B ring). A key DMAP-mediated oxa-Michael/aldol cascade reaction was developed to install the tetrahydroxanthone fragment (E-F ring). This approach provides a new solution to prepare its derivatives and structurally related natural products.
- Dai, Yihua,Ma, Feixia,Shen, Yanfang,Xie, Tao,Gao, Shuanhu
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supporting information
p. 2872 - 2875
(2018/05/29)
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- Tuning of β-glucosidase and α-galactosidase inhibition by generation and in situ screening of a library of pyrrolidine-triazole hybrid molecules
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The preliminary screening of two libraries of epimeric (pyrrolidin-2-yl)triazoles (14a-s and 22a-s), generated via click chemistry, allowed the rapid identification of four α-galactosidase (coffee beans) inhibitors (22b,k,p,r) and two β-glucosidase (almond) inhibitors (14b,f) in the low μM range. The additional biological analysis of 14b,f towards β-glucocerebrosidase (human lysosomal β-glucosidase), as target enzyme for Gaucher disease, showed a good correlation with the inhibition results obtained for the plant (almond) enzyme. Surprisingly, although these compounds showed inhibition towards β-glucocerebrosidase as acid hydrolase, they did not inhibit bovine liver β-glucosidase as neutral hydrolase. In contrast to what was observed for β-glucosidase inhibition, the coffee bean α-galactosidase inhibitors of the epimeric library (22b,k,p,r) only showed weak inhibition towards human lysosomal α-galactosidase.
- Martínez-Bailén, Macarena,Carmona, Ana T.,Moreno-Clavijo, Elena,Robina, Inmaculada,Ide, Daisuke,Kato, Atsushi,Moreno-Vargas, Antonio J.
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p. 532 - 542
(2017/07/11)
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- One-pot synthesis of 2,3-difunctionalized indoles: Via Rh(III)-catalyzed carbenoid insertion C-H activation/cyclization
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Reported herein is the first Rh(iii)-catalyzed carbenoid insertion C-H activation/cyclization of N-arylureas and α-diazo β-keto esters. The redox-neutral reaction has the following features: good to excellent yields, broad substrate/functional group tolerance, exclusive regioselectivity, and no need for additional oxidants or additives, which render this methodology as a more efficient and versatile alternative to the existing methods for the synthesis of 2,3-difunctionalized indoles.
- Lv, Honggui,Shi, Jingjing,Wu, Bo,Guo, Yujuan,Huang, Junjun,Yi, Wei
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supporting information
p. 8054 - 8058
(2017/10/13)
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- Direct Carboxylation of the Diazo Group ipso-C(sp2)-H bond with Carbon Dioxide: Access to Unsymmetrical Diazomalonates and Derivatives
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The direct carboxylation of the ipso-C(sp2)-H bond of a diazo compound with carbon dioxide under mild reaction conditions is described. This method is transition-metal-free, uses a weak base, and proceeds at ambient temperature under atmospheric pressure in carbon dioxide. The carboxylation exhibits high reactivity and is amenable to subsequent diversification. A series of unsymmetrical 1,3-diester/keto/amide diazo compounds are obtained with moderate to excellent yields (up to 99%) with good functional group compatibility.
- Liu, Qianyi,Li, Man,Xiong, Rui,Mo, Fanyang
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supporting information
p. 6756 - 6759
(2017/12/26)
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- A tunable copper-catalyzed multicomponent reaction towards alkaloid-inspired indole/lactam polycycles
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A versatile copper(i)-catalyzed cascade multicomponent reaction strategy between readily available (Z)-3-iodoacrylic acids, terminal alkynes, and primary amines is reported, leading to a great diversity of complex heterocyclic backbones based on biorelevant indole/lactam scaffolds.
- Mardjan,Perie,Parrain,Commeiras
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supporting information
p. 3304 - 3309
(2017/04/21)
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- Novel synthetic approach to alfaprostol key intermediates via Stille coupling with an alkyne
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Novel intermediates based on the Corey skeleton for preparation of the ω-chain of non-halogenated unnatural prostaglandin analogues containing a triple bond at position 13–14 (PG numbering) were synthesized. The utilization of a novel synthetic approach towards a new tin intermediate, and subsequent Stille coupling opens up new possibilities for preparing these important pharmaceutical intermediates.
- Monteiro, Sara,Imramovsky, Ale?,Pauk, Karel,Pavlík, Jan
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supporting information
p. 2228 - 2231
(2017/05/16)
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- Rh(I)-Catalyzed Arylation of α-Diazo Phosphonates with Aryl Boronic Acids: Synthesis of Diarylmethylphosphonates
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An efficient synthetic method for diarylmethylphosphonates is presented. A series of phosphonate derivatives with diverse functional groups can be accessed via a rhodium catalyzed cross-coupling reaction between α-diazo phosphonates and aryl boronic acids. Migratory insertion of rhodium carbene intermediates is postulated to be the critical step in this transformation.
- Zhou, Yujing,Zhang, Yan,Wang, Jianbo
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p. 621 - 627
(2017/05/29)
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- Fluoride-Mediated Dephosphonylation of α-Diazo-β-carbonyl Phosphonates
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The possibility of fluoride-mediated selective dephosphonylation of α-diazo-β-carbonyl phosphonates such as the Ohira-Bestmann reagent has been proposed and executed. The resulting α-diazocarbonyl intermediates undergo a (3 + 2)-cycloaddition at room temperature with conjugated olefins and benzynes. Interestingly, under the current conditions, the resulting cycloaddition products underwent either N-acylation (with excess α-diazo-β-carbonyl phosphonates) or Michael addition (with conjugated olefins).
- Phatake, Ravindra S.,Mullapudi, Venkannababu,Wakchaure, Vivek C.,Ramana, Chepuri V.
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supporting information
p. 372 - 375
(2017/04/21)
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- Rapid and selective synthesis of spiropyrazolines and pyrazolylphthalides employing Seyferth-Gilbert reagent
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An unexpected product-selectivity in the reaction of 2-arylideneindane-1,3-dione with dimethyl diazomethylphosphonate leading to the formation of two different types of products is reported. The reaction carried out in acetone in the presence of catalytic amount of cesium fluoride afforded spiropyrazoline phosphonates via 1,3-dipolar cycloaddition reaction, whereas the reaction in methanol yielded an interesting class of pyrazolylphthalides. This strategy provides an efficient alternative method for the construction of pyrazolylphthalides, and moreover, the process is general, works under mild conditions, and exhibits high functional group compatibility.
- Gupta, Ashis Kumar,Vaishanv, Narendra Kumar,Kant, Ruchir,Mohanan, Kishor
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supporting information
p. 6411 - 6415
(2017/08/10)
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- Backbone-Fluorinated 1,2,3-Triazole-Containing Dipeptide Surrogates
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The 1,2,3-triazole moiety can be incorporated as a peptide bond bioisostere to provide protease resistance in peptidomimetics. Herein, we report the synthesis of peptidomimetic building blocks containing backbone-fluorinated 1,4-disubstituted 1,2,3-triazole moieties. Synthetic protocols for the preparation of various Xaa-Gly dipeptide surrogates in the form of Xaa-ψ[triazole]-F2Gly building blocks were established, and selected examples were introduced into the endogenous peptide opioid receptor ligand Leu-enkephalin as a model compound.
- Engel-Andreasen, Jens,Wellh?fer, Isabelle,Wich, Kathrine,Olsen, Christian A.
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p. 11613 - 11619
(2017/11/10)
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- Remote Cooperative Group Strategy Enables Ligands for Accelerative Asymmetric Gold Catalysis
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An accelerative asymmetric gold catalysis is achieved for the first time via chiral ligand metal cooperation. An asymmetrically positioned remote amide group in the designed chiral binaphthyl-based ligand plays the essential role of a general base catalyst and selectively accelerates the cyclizations of 4-allen-1-ols into one prochiral allene face. The reactions are mostly highly enantioselective with achiral substrates, and due to the accelerated nature of the catalysis catalyst loadings as low as 100 ppm are allowed. With a pre-existing chiral center at any of the backbone sp3-carbons, the reaction remained highly efficient and most importantly maintained excellent allene facial selectivities regardless of the substrate stereochemistry. By using different combinations of ligand and substrate enantiomers, it is now possible to access all four stereoisomers of versatile 2-vinyltetrahydrofurans with exceedingly high selectivity. The underpinning design of this chemistry reveals a novel and conceptually distinctive strategy to tackle challenging asymmetric gold catalysis, which to date has relied on decelerative asymmetric steric hindrance approaches.
- Wang, Zhixun,Nicolini, Corrado,Hervieu, Cedric,Wong, Yuk-Fai,Zanoni, Giuseppe,Zhang, Liming
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supporting information
p. 16064 - 16067
(2017/11/22)
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- 1,2,3-triazole heterocyclic compound, preparation method and application thereof
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The invention provides a 1,2,3-triazole heterocyclic compound, a preparation method and an application thereof. According to the invention, the 1,2,3-triazole heterocyclic compound has a structural general formula in a specification: through cellular level experiment, the provided 1,2,3-triazole heterocyclic compound can inhibit propagation of K562-3d, HL60, and KG1a cells, in an experiment 2, under condition that the medical concentration of the compound is lower than a positive contrast drug imatinib, the effect for inhibiting the propagation of K562-3d, HL60, and KG1a cells can be realized, and the 1,2,3-triazole heterocyclic compound can be used for treating leukemia.
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Paragraph 0080; 0081; 0082
(2017/02/17)
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- Synthesis and cytotoxicity evaluation of aryl triazolic derivatives and their hydroxymethine homologues against B16 melanoma cell line
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In this manuscript we describe synthesis and cytotoxicity evaluation of some triazolic derivatives against B16 melanoma cell line. For this purpose, we transformed a set of aromatic aldehydes into terminal alkynes, using Besthmann-Ohira reagent, and we made the corresponding hydroxymethyl homologated alkynes by an acetylene Grignard reagent. These generated two sets of alkynes were then subjected to a copper(I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC) using a solid-supported catalyst (Amberlyst A-21?CuI), with a third set composed of organic azides. Synthesized triazoles were then tested in?vitro against B16 melanoma cell line. Amongst them, compounds a1b1 (R1?=?p-nitrophenyl, R2?=?benzyl), a4b1 (R1?=?naphthyl, R2?=?benzyl) and a4b5 (R1?=?naphthyl, R2?=?(R/S)- dioxolane) showed the best activity against B16 melanoma cells, with IC50of 5.12, 3.89 and 6.60?μM respectively.
- Kalhor-Monfared, Shiva,Beauvineau, Claire,Scherman, Daniel,Girard, Christian
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supporting information
p. 436 - 441
(2016/07/15)
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- Synthesis of a Novel Rhizobitoxine-Like Triazole-Containing Amino Acid
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The synthesis of the four stereoisomers of a new 1,2,3-triazole analogue of rhizobitoxine from serine is described. The key step is a Huisgen 1,3-dipolar cycloaddition on an ethynylglycine synthon.
- Boibessot, Thibaut,Bénimèlis, David,Jean, Marion,Benfodda, Zohra,Meffre, Patrick
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supporting information
p. 2685 - 2688
(2016/11/30)
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- Synthesis of Allenylphosphonates through Cu(I)-Catalyzed Coupling of Terminal Alkynes with Diazophosphonates
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Through the Cu(I)-catalyzed coupling of diazophosphonates with terminal alkynes, an efficient method for the synthesis of allenylphosphonates has been developed. Simple and inexpensive CuI is used as the catalyst and the reaction is conducted under mild conditions.
- Wu, Chenggui,Ye, Fei,Wu, Guojiao,Xu, Shuai,Deng, Guisheng,Zhang, Yan,Wang, Jianbo
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p. 751 - 760
(2016/02/27)
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- Cu(I)-Catalyzed Tandem Reaction of Carbene Coupling and Horner-Wadsworth-Emmons Type Olefination: Access toward Enynes
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A novel strategy to synthesize 1,3-enynes has been successfully developed based on Cu(I)-catalyzed cross-coupling of α-diazo phosphonates and alkynes with a subsequent Horner-Wadsworth-Emmons (HWE) type reaction. This method provides straightforward access to conjugated enynes with high efficiency, good stereoselectivity and excellent functional group compatibility. Copper(I) carbene migratory insertion plays a crucial role in this transformation.
- Zhou, Yujing,Ye, Fei,Zhou, Qi,Zhang, Yan,Wang, Jianbo
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supporting information
p. 2024 - 2027
(2016/06/01)
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- Ir(III)-Catalyzed Synthesis of Isoquinoline N-Oxides from Aryloxime and α-Diazocarbonyl Compounds
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An efficient Ir(III)-catalyzed C-H activation and annulations of aryloxime with α-diazocarbonyl compounds has been developed for the synthesis of substituted isoquinoline N-oxides. The reaction proceeds under mild atmospheric conditions, without any external oxidants and releases N2 and H2O as the byproducts. In addition, synthetic applications of the N-oxide products have been established by performing further functionalization. An interesting dimeric iridacyclic complex allied through a bis-silver carboxylate bridge has been isolated that efficiently catalyzed the reaction.
- Phatake, Ravindra S.,Patel, Pitambar,Ramana, Chepuri V.
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supporting information
p. 292 - 295
(2016/02/03)
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- Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor
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PSD-95 PDZ domains are biologically important and promising drug targets. Here, we discover a triazole-based peptidomimetic, 10, by 'click chemistry'. Compound 10 inhibits the PDZ2/GluN2B interaction with affinity similar to tripeptide SAV and better than current small-molecules. Thus, 10 represents a new class of PSD-95 PDZ inhibitors.
- Bach, Anders,Pedersen, Thomas B.,Str?mgaard, Kristian
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supporting information
p. 531 - 536
(2016/04/01)
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- Ir(III)-Catalyzed Carbenoid Functionalization of Benzamides: Synthesis of N-Methoxyisoquinolinediones and N-Methoxyisoquinolinones
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A mild and efficient Ir(III)-catalyzed C-H carbenoid functionalization strategy has been developed to access N-methoxyisoquinolinediones and N-methoxyisoquinolinones. The reaction proceeds efficiently in high yield at room temperature over a broad range of substrates without requirement of any additional oxidants or a base.
- Phatake, Ravindra S.,Patel, Pitambar,Ramana, Chepuri V.
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supporting information
p. 2828 - 2831
(2016/07/06)
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- Geminal difunctionalization of α-diazo arylmethylphosphonates: Synthesis of fluorinated phosphonates
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A general approach towards diverse fluorinated phosphonates via geminal difunctionalization reactions of α-diazo arylmethylphosphonates is described. The diazo functionality (RR′CN2) is successfully converted to RR′CF2, RR′CHF, RR′CFBr or RR′CFNR′′2 groups by employing different fluorination reagents. A variety of fluorinated organophosphorus compounds were readily accessed in good to excellent yields from a common type of precursor.
- Zhou, Yujing,Zhang, Yan,Wang, Jianbo
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p. 10444 - 10453
(2016/11/18)
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- PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, pharmaceutical compositions containing them, and to their use in therapy for the prevention treatment of cancer.
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Page/Page column 82
(2015/07/07)
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- PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, to pharmaceutical compositions containing them, and to their use in therapy for the prevention or treatment of cancer.
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Page/Page column 78; 79
(2015/07/07)
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- Organocatalytic enantioselective 1,3-dipolar cycloadditions between seyferth-gilbert reagent and isatylidene malononitriles: Synthesis of chiral spiro-phosphonylpyrazoline-oxindoles
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A new method has been developed for the catalytic enantioselective 1,3-dipolar cycloaddition of the Seyferth-Gilbert reagent (SGR) to isatylidene malononitriles using a cinchona alkaloid derivative as a catalyst. This method allowed for the synthesis of a series of chiral spiro-phosphonylpyrazoline-oxindoles in good yields with excellent enantioselectivities. The synthetic utility of this method was further demonstrated by its use in a three-component domino reaction involving isatin, malononitrile, and SGR based on sequential Knoevenagel condensation and 1,3-dipolar cycloaddition reactions.
- Du, Taiping,Du, Fei,Ning, Yanqiang,Peng, Yungui
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supporting information
p. 1308 - 1311
(2015/03/14)
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- Rh(III)-catalyzed chelation-assisted intermolecular carbenoid functionalization of α-imino Csp3-H bonds
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A Rh(iii)-catalyzed cross-coupling/cyclization cascade of α-imino Csp3-H bonds with donor/acceptor α-acyl diazocarbonyl compounds has been developed. This novel transformation involves ligand-directed Csp3-H bond functionalization with carbenoids under the pyridine-chelation assistance, and offered an efficient access to synthetically versatile polysubstituted N-(2-pyridyl)pyrroles with a broad range of functional group tolerance.
- Chen, Xun,Xie, Ying,Xiao, Xinsheng,Li, Guoqiang,Deng, Yuanfu,Jiang, Huanfeng,Zeng, Wei
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supporting information
p. 15328 - 15331
(2015/10/20)
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- BIOREVERSABLE PROMOIETIES FOR NITROGEN-CONTAINING AND HYDROXYL-CONTAINING DRUGS
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Disclosed are promoieties of the following formula which can be used to form prodrugs of nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent: (I) and pharmaceutical compositions comprising the prodrugs.
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Page/Page column 148; 149
(2015/06/18)
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- Synthesis of Alkenylphosphonates through Palladium-Catalyzed Coupling of α-Diazo Phosphonates with Benzyl or Allyl Halides
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An efficient method for the synthesis of organophosphonates through palladium-catalyzed coupling of α-diazo phosphonates with benzyl or allyl halides has been developed. Trisubstituted alkenylphosphonates bearing versatile functional groups can be easily accessed in good yields and with excellent stereoselectivity through this method. Moreover, with similar strategy α-substituted vinylphosphonates can also be attained by the palladium-catalyzed coupling reaction of N-tosylhydrazones and aryl bromides. Migratory insertion of palladium carbene is proposed as the key step in this reaction.
- Zhou, Yujing,Ye, Fei,Wang, Xi,Xu, Shuai,Zhang, Yan,Wang, Jianbo
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p. 6109 - 6118
(2015/06/30)
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- TETRACYCLIC CDK9 KINASE INHIBITORS
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Disclosed are compounds of Formula (Ia), and pharmaceutically acceptable salts thereof, wherein X, Y, R1, R2, R3A, R3B, and R4 are as described herein. The compounds may be used as agents in the treatment of diseases, including cancer. Also disclosed are pharmaceutical compositions comprising one or more compounds of Formula (Ia).
- -
-
Paragraph 1174
(2015/09/22)
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- Synthesis and antiviral evaluation of 4′-(1,2,3-triazol-1-yl) thymidines
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Non-obligate chain terminating nucleosides with a linear substituent (azido or ethynyl group) at the 4′ position represent an important class of compounds in antiviral discovery, particularly against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). We have previously shown that 3′-azidothymidine (AZT)-derived 1,2,3-triazoles can be potent inhibitors of HIV-1. To gauge the medicinal chemistry impact of functionalizing the 4′-linear substituent and possibly generate novel antiviral nucleoside scaffolds, we have explored azide-alkyne cycloaddition reactions with 4′-azidothymidine (ADRT). The Ru-mediated reaction failed and the Cu-catalyzed variant generated 1,2,3-triazoles (9a-y) with only modest yields and efficiencies, indicating a substantial steric barrier around the 4′-azido group. Antiviral screening identified a few triazole analogues moderately active against HIV-1 (18-62% inhibition at 10 μM) and/or influenza A virus (15-50% inhibition at 10 μM), and none active against West Nile virus (WNV) or HCV. These results suggest that the linear 4′ azido group of ADRT may be essential for target binding and that its chemical manipulation could largely compromise antiviral potency. This journal is the Partner Organisations 2014.
- Vernekar, Sanjeev Kumar V.,Qiu, Li,Zacharias, Jeana,Geraghty, Robert J.,Wang, Zhengqiang
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supporting information
p. 603 - 608
(2014/05/06)
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- IMIDAZOPYRIDINE COMPOUNDS AND USES THEREOF
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This invention generally relates to substituted imidazopyridine compounds, particularly substituted 4-(imidazo[1,2-a]pyridin-2-yl)benzamide compounds and salts thereof. This invention also relates to pharmaceutical compositions and kits comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), processes for making such a compound, and intermediates used in such processes.
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Paragraph 217
(2014/08/19)
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- ANTIBACTERIAL AGENTS
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Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts and esters thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
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Page/Page column 44; 45
(2014/10/18)
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- Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment
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The antimicrobial peptide nisin is a promising template for designing novel peptide-based antibiotics to improve its drug-like properties. First steps in that direction represent the synthesis of hybrid nisin derivatives that contain a native nisin ABC-part and synthesized cross-stapled DE-ring fragments and are described here. The biological activity of the newly synthesized nisin derivatives was evaluated in order to compare the bioactivity of the synthetic DE-ring containing mimic and native lanthionine-bridged DE-ring containing nisin. The native nisin ABC-ring system was obtained via chymotrypsin digestion of full-length nisin, and was subsequently functionalized at the C-terminal carboxylate with two different amino alkyne moieties. Next, nisin hybrids were successfully prepared using Cu(I)-catalyzed azide alkyne cycloaddition 'click' chemistry by chemo-selective ligation of the ABC-alkyne with the N-terminal azido functionalized dicarba-DE ring mimic. The newly synthesized compounds were active as potent lipid II binders and retained antimicrobial activity in a growth inhibition assay. However, pore formation was not observed, possibly either due to the different character of the 'staples' as compared to the parent sulfides, or due to the triazole moiety as a sub-optimal amide bond isostere.
- Slootweg, Jack C.,Peters, Nienke,Quarles Van Ufford,Breukink, Eefjan,Liskamp, Rob M.J.,Rijkers, Dirk T.S.
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supporting information
p. 5345 - 5353
(2014/12/11)
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- Synthesis of Aryldiazoacetates through Palladium(0)-Catalyzed Deacylative Cross-Coupling of Aryl Iodides with Acyldiazoacetates
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Palladium(0)-catalyzed deacylative cross-coupling of aryl iodides and acyldiazocarbonyl compounds can be achieved at room temperature under mild reaction conditions. The coupling reaction represents a highly efficient and general method for the synthesis of aryldiazocarbonyl compounds, which have found wide and increasing applications as precursors for generating donor/acceptor-substituted metallocarbenes.
- Ye, Fei,Wang, Chengpeng,Zhang, Yan,Wang, Jianbo
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supporting information
p. 11625 - 11628
(2016/02/19)
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