- Identification and Structure–Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
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The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small-molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure- and ligand-based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4-aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series.
- Robaa, Dina,Wagner, Tobias,Luise, Chiara,Carlino, Luca,McMillan, Joel,Flaig, Ralf,Schüle, Roland,Jung, Manfred,Sippl, Wolfgang
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- New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis
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Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.
- Tazarki, Helmi,Zeinyeh, Wael,Esvan, Yannick J.,Knapp, Stefan,Chatterjee, Deep,Schr?der, Martin,Joerger, Andreas C.,Khiari, Jameleddine,Josselin, Béatrice,Baratte, Blandine,Bach, Stéphane,Ruchaud, Sandrine,Anizon, Fabrice,Giraud, Francis,Moreau, Pascale
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p. 304 - 317
(2019/02/07)
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- Heterogeneously catalyzed selective hydrogenation of amides to alcohols and amines
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We report the heterogeneously catalyzed hydrogenation of amides to form alcohols and amines. This C-N bond cleavage reaction is catalyzed by silver on γ-alumina, proceeds smoothly in high yields and 100% selectivity, and is effective for both benzamides and aliphatic amides. This is in contrast to amide hydrogenation catalyzed by heterogeneous catalysts, which generally proceeds via C-O bond cleavage. Recycling experiments show that the catalyst Ag/γ-Al2O3 can be easily recovered and regenerated without decrease in catalytic activity.
- Xie, Yinjun,Hu, Peng,Bendikov, Tatyana,Milstein, David
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p. 2784 - 2788
(2018/06/18)
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- Highly efficient reduction of carbonyls, azides, and benzyl halides by NaBH4 in water catalyzed by PANF-immobilized quaternary ammonium salts
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A series of polyacrylonitrile fiber-supported quaternary ammonium salts (PANF-QAS) were prepared and applied to the catalytic reduction of aldehydes, ketones, azides, and benzyl halides in water using NaBH4 as the reducing reagent in a highly efficient, economic, and environmentally benign way. The structure-activity relationships were investigated, which showed that the catalysts made up of quaternary ammonium salts with longer alkyl chains, larger cationic radii and better lipophilicity speed up the reduction reaction to afford the products in excellent yield. Moreover, the optimized catalyst can be applied to the reduction of 1-naphthaldehyde in a continuous flow process with outstanding reactivity and recyclability.
- Du, Jianguo,Xu, Gang,Lin, Huikun,Wang, Guangwei,Tao, Minli,Zhang, Wenqin
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supporting information
p. 2726 - 2735
(2016/05/24)
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- METHOD FOR PRODUCING N,N-SUBSTITUTED-1,3-PROPANDIAMINES
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The present invention relates to a process for preparing N,N-substituted 1,3-propanediamine by a) reacting secondary amine with acrolein at a temperature of from (?50) to 100° C. and a pressure of from 0.01 to 300 bar, andb) reacting the reaction mixture obtained in stage a) with hydrogen and ammonia in the presence of a hydrogenation catalyst at a temperature of from 40 to 400° C. and a pressure of from 1 to 400 bar, wherein the molar ratio of secondary amine to acrolein in stage a) is 2:1 or more and the hydrogenation catalyst used in stage b) comprises cobalt. In a preferred embodiment, acrolein which has been obtained from glycerol based on renewable raw materials is used. The invention further relates to the use of N,N-dimethyl-1,3-propanediamine (DMAPA) based on renewable raw materials as a feedstock for lubricant soaps and other detergents, coagulants, polymers and comb polymers. In a further preferred embodiment, stage b) is performed in the presence of water.
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Page/Page column 9
(2011/04/18)
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- 2-aminobenzoxazole derivatives and combinatorial libraries thereof
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The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula: wherein R1 to R4 and Z have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminobenzoxazole derivative compounds.
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- 2-aminopyridine derivatives and combinatorial libraries thereof
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The present invention relates to novel 2-aminopyridine derivative compounds of the following formula: wherein R1to R5have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminopyridine derivative compounds.
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- Hair revitalizing tonic composition containing a 2,2-dimethylpropanediol compound and use thereof
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Disclosed is a hair revitalizing tonic composition containing a dimethylpropanediol derivative of the formula: wherein R1and R2are each independently a C1-30hydrocarbon group which may be substituted, or a five- or six-membered heterocyclic group which contains1to4heteroatoms selected from oxygen, sulfur and nitrogen atoms and which may be substituted, R3is hydrogen atom, an alkyl group which may be substituted, an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a carbamoyl group which may be substituted, and a and b are each 0 or 1, as well as a method for effecting hair growth promotion, hair growth stimulation, or hair loss prevention in mammals by using such a hair revitalizing tonic composition. Also disclosed is the use of a compound of formula (I) in the preparation of a hair revitalizing tonic composition. Thus, this invention can provide an excellent means of hair revitalization or hair loss prevention in mammals.
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- NUCLEOPHILIC CLEAVAGE AND FORMATION OF SATURATED HETEROCYCLES. XII. REACTIVITY OF SMALL HETEROCYCLES TOWARD AMINOLYSIS AND HYDROLYSIS
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The cleavage of four-membered saturated heterocycles proceeds via a more product-like transition state than that of three-membered rings.General acid catalysis is characteristic of oxygen heterocycles, but in the case of nitrogen heterocycles catalysis is specific.The reactivity of amines in the cleavage of azetidines is linearly dependent on their pKa values, primary and secondary amines comprising separate reaction series.
- Bobylev, V. A.,Veselkov, N. Yu.,Dalin, A. R.,Sharikov, F. Yu.
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p. 1700 - 1713
(2007/10/02)
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- Substituted 1,3-dialkylpyrido[4,3-d]pyrimidine-2,4-diones
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The present invention relates to a novel pyrido[4,3-d]pyrimidine derivative having the formula (I): STR1 wherein each of R1 and R2, which may be the same or different, is a lower alkyl group; R3 is hydrogen, halogen, hydroxy, amino, hydroxyamino, imino, hydrazino or a lower alkylamino group which may optionally have hydroxy, amino or a lower alkylamino group; and R4 is hydrogen, amino, --NH? or a lower alkyl group which may optionally have hydroxy, amino or a lower alkylamino group; and pharmaceutically acceptable salt thereof. These compounds are useful as anti-allergic agents, for example, for the treatment of bronchial asthma, urticaria, allergic rhinitis, allergic dermatoses or allergic conjunctivitis.
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- Substituted sulfonamidobenzamides and method of treating arrhythmias
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Novel substituted sulfonamidobenzamides are described as useful antiarrhythmic agents. Their use in the treatment of cardiac arrhythmias, especially re-entrant arrhythmias, via the prolongation of the action potential of cardiac tissue is provided. Pharmaceutical formulations containing such compounds are also disclosed.
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- Substituted sulfonamidobenzamides, antiarrhythmic agents and compositions thereof
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Novel substituted sulfonamidobenzamides are described as useful antiarrhythmic agents. Their use in the treatment of cardiac arrhythmias, especially re-entrant arrhythmias, via the prolongation of the action potential of cardiac tissue is provided. Pharmaceutical formulations containing such compounds are also disclosed.
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- Phthalocyanines
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Storage-stable aqueous compositions containing dissolved water-soluble novel acid addition salts of poly(N-substituted sulfonamido) phthalocyanines which are prepared by the interaction of a single acid or a mixture of acids and poly(N-substituted sulfonamido) phthalocyanines, are useful for direct dyeing, particularly the dyeing of cellulose.
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- Novel monoazo and disazo colorants
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This invention relates to novel (N-substituted sulfonamido) monoazo and disazo compounds, to acid-addition salts of said azo compounds which are useful as direct dyes particularly in the dyeing of cellulose, to novel (N-substituted sulfonamido) substituted nitrobenzene, aniline and acetanilide intermediates to said azo compounds and to methods of preparation of said azo compounds and said intermediates to said azo compounds.
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- N-Aminoalkylenesulfonamido substituted monoazo colorants
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This invention relates to novel mixtures consisting essentially of monoazo compounds and disazo compounds which are substituted with x (N-substituted sulfonamido) groups, to acid-addition salts of said azo compounds, useful as direct dyes particularly in the dyeing of cellulose, and to methods of preparation of said mixtures of (N-substituted sulfonamido) substituted monoazo and disazo compounds.
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- Novel compositions and processes
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Storage-stable aqueous compositions containing dissolved water-soluble novel acid addition salts of poly(N-substituted sulfonamido) phthalocyanines which are prepared by the interaction of a single acid or a mixture of acids and poly(N-substituted sulfonamido) phthalocyanines, are useful for direct dyeing, particularly the dyeing of cellulose.
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- Long-range anisotropic effects of long chain amides
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In 1H-NMR spectra of amids with long-chain aliphatic N-substituents one observes - despite of the free mobility of the aliphatic chain - splitting of the signals of the terminal methyl groups which is caused by the hindered rotation of the amide bond. - Keywords: Amides; Hindered rotation; 1H-NMR
- Budzikiewicz, Herbert,Vieth, Peter-Eric,Krueger, Uwe
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p. 825 - 840
(2007/10/02)
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- Pyrazine derivatives
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Pyrazine derivatives by the formula STR1 are disclosed. In the above formula, R1 and R2, which may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group, a phenoxy group, a mercapto group, a lower alkylthio group, a phenyl lower alkylthio group, a phenylthio group, an amino group, a substituted amino group, a lower alkyl group, a carbamoyl group or a sulfamoyl group; R3 represents a lower alkoxy group; R4, R5, and R6, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl lower alkyl group, or a phenyl group; and A represents a lower alkylene group; said R4 and A, said R5 and A, said R4 and R5, or said R5 and R6 may form a 5-membered or 6-membered nitrogen-containing heterocyclic ring which may further contain a hetero-atom together with nitrogen atom, and the pharmacologically acceptable non-toxic salts thereof. The compounds of this invention have a strong and selective antiematic activity and an effect of stimulating the gastric motility.
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- 2'-(4,6-Disubstituted)-s-triazin-2-yl)amino-6'-dialkylamino flurans
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Fluorans useful as color precursors, particularly in the art of carbonless duplicating are normally colorless and are represented by the structural formula STR1 wherein R represents non-tertiary alkyl of one to four carbon atoms; R1 and R2 represent hydrogen or non-tertiary alkyl of one to four carbon atoms; R3 and R4 represent chlorine, NH2 or one of the groups --NR5 -(lower-alkylene)-N(R6)(R7), --NR5 -(lower-alkylene-N(R8)(R9)(R10) An, -NR5 -(lower-alkylene)-OH, -NR5 -(lower-alkylene) STR2 --NR5 -(HSO3 -C6 H4) or --O-(lower-alkylene)-N(R8)(R9) in which R5, R6 and R7 represent hydrogen or non-tertiary alkyl of one to four carbon atoms; R8 and R9 represent non-tertiary alkyl of one to four carbon atoms; R10 represents non-tertiary alkyl of one to four carbon atoms, benzyl or benzyl substituted in the benzene ring by one or two of halo or alkyl of one to three carbon atoms; and An represents an anion.
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- Triazinyl-benzofluorans
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Fluorans useful as color precursors, particularly in the art of carbonless duplicating are normally colorless and are represented by the structural formula STR1 wherein R represents non-tertiary alkyl of one to four carbon atoms; R1 and R2 represent hydrogen or non-tertiary alkyl of one to four carbon atoms; R3 and R4 represent chlorine, or one of the groups --NR5 -(lower-alkylene)-N(R6)(R7) or --NR5 -(lower-alkylene-N+ (R8)(R9)(R10) An- , in which R5, R6 and R7 represent hydrogen or non-tertiary alkyl of one to four carbon atoms; R8 and R9 represent non-tertiary alkyl of one to four carbon atoms, R10 represents non-tertiary alkyl of one to four carbon atoms, benzyl or benzyl substituted in the benzene ring by one or two of halo or alkyl of one to three carbon atoms; and An represents an anion.
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- Triazinyl-benzofluorans
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Fluorans useful as color precursors, particularly in the art of carbonless duplicating are normally colorless and are represented by the structural formula STR1 wherein R represents non-tertiary alkyl of one to four carbon atoms; R1 represents hydrogen or non-tertiary alkyl of one to four carbon atoms; R2 and R3 represent chlorine or one of the groups --NR4 --(lower-alkylene)--N(R5)(R6) or --NR4 --(lower-alkylene)--N+(R7)(R8)(R9)An- In which R4, R5 and R6 represent hydrogen or non-tertiary alkyl of one to four carbon atoms; R7 and R8 represent non-tertiary alkyl of one to four carbon atoms; R9 represents non-tertiary alkyl of one to four carbon atoms, benzyl or benzyl substituted in the benzene ring by one or two of halo or alkyl of one to three carbon atoms; and An represents an anion.
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