- MACROCYCLIC INHIBITORS OF PEPTIDYLARGININE DEIMINASES
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The present disclosure relates to novel compounds for use in therapeutic treatement of a disease associated with peptidylarginine deiminases (PADs), such as peptidylarginine deiminase type 4 (PAD4). The present disclosure also relates to processes and intermediates for the preparation of such compounds, methods of using such compounds and pharmaceutical compositions comprising the compounds described herein.
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Page/Page column 259; 372
(2021/11/06)
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- Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs
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A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.
- Nicolaou, Kyriacos C.,Vourloumis, Dionisios,Totokotsopoulos, Sotirios,Papakyriakou, Athanasios,Karsunky, Holger,Fernando, Hanan,Gavrilyuk, Julia,Webb, Damien,Stepan, Antonia F.
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- (2R,1'S,2'R)- And (2S,1'S,2'R)-3-[2-mono(di,tri)fluoromethylcyclopropyl] alanines and their incorporation into hormaomycin analogues
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Efficient and scalable syntheses of enantiomerically pure (2 R ,1' S ,2' R )- and (2 S ,1' S ,2' R )-3-[2-mono(di,tri)fluoromethylcyclopropyl] alanines 9a - c , as well as allo-D-threonine ( 4 ) and ( 2 S,3R)-β-methylphenylalanine (3), using the Belokon' approach with (S )- and (R )-2-[( N-benzylprolyl)amino]benzophenone [(S)- and (R)-10 ] as reusable chiral auxiliaries have been developed. Three new fluoromethyl analogues of the naturally occurring octadepsipeptide hormaomycin ( 1 ) with (fluoromethylcyclopropyl) alanine moieties have been synthesized and subjected to preliminary tests of their antibiotic activity.
- De Meijere, Armin,Kozhushkov, Sergei I.,Yufit, Dmitrii S.,Grosse, Christian,Kaiser, Marcel,Raev, Vitaly A.
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supporting information
p. 2844 - 2857
(2015/02/19)
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- Synthesis and radical polymerization of various 2-cyclopropylacrylates
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Fourteen new alkyl 2-cyclopropylacrylates 1a-n with various substituents R1-R5 were synthesized from readily available precursors by applying standard transformations such as cyanohydrin formation from an aldehyde, alcoholysis to an α-hydroxycarboxylic ester, oxidation and Wittig methylenation of an α-oxocarboxylic ester. Overall yields ranged from 33 to 54%. A new method for the hydrolysis of dimethyl cyclopropanedicarboxylates to the corresponding half-esters was developed. The α-oxocarboxylates 7g-n were prepared by dirhodium tetraacetate catalyzed cyclopropanation of alkenes 8g-n with methyl or ethyl diazopyruvate in 32-58% yield. The monomers 1a-n were characterized by 1H, 13C NMR spectroscopy, mass spectrometry and elemental analysis. The radical homopolymerizations of 1a-n were carried out with 2,2′- azabisisobutyronitrile (AIBN) as initiator in chlorobenzene at 65 °C. The highest polymer yields were obtained in the polymerizations of If and 1h or 1k and 11, i.e. from monomers with an annelated five- or six-membered ring. In the case of 1h and 1k, both the polymer yields (99 and 98%, respectively) and the glass transition temperatures (Tg) of 57 and 93 °C were significantly higher than those observed for the polymer from 1,1-bis(ethoxycarbonyl)-2-vinylcyclopropane (DECVCP), which was used as a benchmark for the monomer reactivities in the radical polymerizations of all the vinylcyclopropane derivatives 1a-n. The bicyclic monomers 1h and 1k also demonstrated drastically improved reactivities in the radical copolymerization with methyl methacrylate when compared to DECVCP. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- De Meijere, Armin,Bagutski, Viktor,Zeuner, Frank,Fischer, Urs Karl,Rheinberger, Volker,Moszner, Norbert
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p. 3669 - 3678
(2007/10/03)
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- Synthesis and biological evaluation of novel 2-(1H-imidazol-4-yl)cyclopropane carboxylic acids: key intermediates for H3 histamine receptor ligands.
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A new synthetic methodology to provide cis-2-(1H-imidazol-4-yl)-cyclopropane carboxylic acids is described. These cyclopropanes are useful for the preparation of novel H(3) receptor agents.
- Brana, Miguel F,Guisado, Cristina,Fernando Alguacil, Luis,Garrido, Elisa,Perez-Garcia, Carmen,Ruiz-Gayo, Mariano
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p. 3561 - 3563
(2007/10/03)
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- cis-Disubstituted Cyclopropanes via Asymmetric Catalytic Cyclopropenation: Synthesis of Cyclopropyl-dehydroamino Acids and of Dictyopterene C′
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The cyclopropenation of diethoxypropyne (1) with methyl diazoacetate in the presence of [Rh2{(2S)-mepy}4] (mepy = methyl 5-oxopyrrolidine-2-carboxylate) proceeds with >95% ee. The resulting cyclopropenecarboxylate 2 underwent stereos
- Imogai, Hassan,Bernardinelli, Gerald,Graenicher, Christian,Moran, Mary,Rossier, Jean-Claude,Mueller, Paul
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p. 1754 - 1764
(2007/10/03)
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- Controlling π-Facial Diastereoselectivity in the 1,3-Dipolar Cycloadditions of Diazomethane to Chiral Pentenoates and Furanones: Enantioselective Stereodivergent Syntheses of Cyclopropane Hydroxy Acids and Didehydro Amino Acids
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The title compounds have been synthesized in both enantiomeric forms and in good overall yields by using D-glyceraldehyde as the single chiral precursor. The efficiency and usefulness of the synthetic routes have been secured by performing controlled manipulations of the functional groups and by highly stereoselective transformations, namely Wittig-Horner condensations and cyclopropanations. Cyclopropane derivatives have been synthesized through 1,3-dipolar cycloaddition of diazomethane to chiral pentenoates or furanones obtained, in turn, from D-glyceraldehyde. Syn/ anti stereochemistry of the cycloadducts has been unequivocally assigned and rationalized. Since π-facial diastereoselectivity involved in these cycloadditions is the opposite for cyclic and open- chain structures, enantiomeric series of products can be derived.
- Martin-Vila, Marta,Hanafi, Neuh,Jimenez, Jose M.,Alvarez-Larena, Angel,Piniella, Joan F.,Branchadell, Vicenc,Oliva, Antonio,Ortuno, Rosa M.
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p. 3581 - 3589
(2007/10/03)
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- PSEUDOESTERES Y DERIVADOS XXXIII. SINTESIS DE COMPUESTOS CICLOPROPANICOS POR FOTOLISIS DE PIRAZOLINAS OBTENIDAS POR CICLOADICION 1,3-DIPOLAR A LA 5-METOXI-2(5H)-FURANONA
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By cycloaddition of 2-diazopropane to 5-methoxy-2(5H)-furanone (1) two regioisomeric 1-pyrazolines 3 and 4 are stereospecifically obtained.Both isomers give by photolysis, as major or sole compound, the same cyclopropane derivative 7.Hydrolysis of the bicyclic compound 7, followed by esterification, leads to cis open chain derivatives, which are appropiately functionalized for the synthesis of pyrethroids. a similar set of reactions, using diazomethane-d2 as dipolarophile, affords selectively deuterated cyclopropane derivatives.Palabras clave: Cicloadicion 1,3-dipolar, pirazolinas, fotolisis, ciclopropanos, piretroides.
- Farina, F.,Martin, M. V.,Soria, M. L.
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- Asymmetric synthesis of enantiopure (+)-(1S,2S) methyl 2-formylcyclopropanecarboxylate and corresponding (Z) and (E) didehydroamino acid derivatives
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The title cyclopropane aldehyde and didehydroamino acids have been synthesised from (S)-(+)-γ-butyrolactone-γ-carboxylic acid as a chiral precursor.
- Le Corre,Hercouet,Bessieres
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p. 683 - 684
(2007/10/02)
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- Effective uses of dirhodium(II) tetrakis[methyl 2-oxopyrrolidine-5(R or S)-carboxylate] for highly enantioselective intermolecular cyclopropenation reactions
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The title compounds are effective catalysts for intermolecular cyclopropenation reactions of 1-alkynes with diazo esters and diazo amides. Diastereoselectivities achieved from the appropriate match with d- or l-menthyl diazoacetate are 77 to ≥ 94% de. Ena
- Doyle, Michael P.,Protopopova, Marina,Müller, Paul,Ene, Doina,Shapiro, Evgeny A.
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p. 8492 - 8498
(2007/10/02)
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- Synthesis of Methyl (1R,2S)-2-cyclopropanecarboxylate: a Potential Inhibitor of the Enzyme 5-Lipoxygenase
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We describe the synthesis of a novel cyclopropyl analogue of arachidonic acid via a convergent synthesis that employed methyl (1R,2S)-2-formylcyclopropanecarboxylate in conjunction with the ylide from (3Z,6Z)-pentadeca-3,6-dienyl(triphenyl)phosphonium iod
- Butler, Paul I.,Clarke, Trafford,Dell, Colin,Mann, John
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p. 1503 - 1508
(2007/10/02)
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- Stereoselective synthesis of enantiopure cyclopropane didehydroamino acid derivatives: (-)-(Z)-2-benzyloxycarbonylamino-4,5-cyclopropane-2-hexenodioic acid dimethyl ester
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The title amino acid derivative has been synthesized stereoselectively in 40% overall yield from 5-tert-butyldiphenylsilyloxymethyl-2(5H)-furanone used as a chiral precursor.
- Hanafi,Ortuno
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p. 1657 - 1660
(2007/10/02)
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