Highly potent aminopyridines as Syk kinase inhibitors

Castillo, Marcos; Forns, Pilar; Erra, Montse; Mir, Marta; Lopez, Michel Angel; Maldonado, Mónica; Orellana, Adelina; Carreño, Cristina; Ramis, Isabel; Miralpeix, Montserrat; Vidal, Bernat

doi:10.1016/j.bmcl.2012.07.045

Cited by 20 publications

(8 citation statements)

References 10 publications

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“…59 Looking for a Pd-free approach to the synthesis of H 2 tpda, we decided to explore the reactivity of 2-fluoropyridine, which is less toxic than 2-chloropyridine and is a known efficient electrophile in S N Ar reactions with anilines or other amines. [60][61][62][63] The order of addition of the reagents was inspired by the best available method, namely the synthesis of Br 2 H 2 tpda. 42 Thus, the selected base (10 equiv.)…”

Section: Dft Calculationsmentioning

confidence: 99%

Solution structure of a pentachromium(ii) single molecule magnet from DFT calculations, isotopic labelling and multinuclear NMR spectroscopy

et al. 2018

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The structure of pentachromium(ii) extended metal atom chain [Cr(tpda)Cl] (2), which behaves as a single molecule magnet at low temperature, was investigated by Density Functional Theory (DFT) calculations and spectroscopic studies without the constraints of a crystal lattice (Htpda = N,N-bis(pyridin-2-yl)pyridine-2,6-diamine). DFT studies both in the gas phase and including CHCl solvent effects indicate that an unsymmetric structure (C point group), with pairs of formally quadruply-bonded metal ions and one terminal metal center, is slightly more stable (2.9 and 3.9 kcal mol) than a symmetric structure (D point group). Isotopically-labelled samples (2-d and 2-d) have then been prepared to aid in molecular symmetry determination by combined H andH NMR studies in dichloromethane solution. The spectra are strongly suggestive of a symmetric (D) framework, indicating fast shuttling between the two unsymmetric forms over the timescale of NMR experiments. Procedures for a high-yield Pd-free synthesis of Htpda and for site-selective post-synthetic H/D exchange of aromatic Htpda hydrogens are also reported.

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Section: Dft Calculationsmentioning

confidence: 99%

Solution structure of a pentachromium(ii) single molecule magnet from DFT calculations, isotopic labelling and multinuclear NMR spectroscopy

et al. 2018

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“…The structure of Vam3 and resveratrol was constructed using Mastro [ 25 ], while the ligands OSB and 1B6 were retrieved from the Protein Data Bank (PDB code: 4F4P and 4Y0T, respectively) [ 10 , 12 ]. All the ligands were prepared by using the LigPrep [ 26 ] and then to proceed with stereoisomer generation, neutralization of charged structures and determination of the most probable ionization state at pH 7.2 ± 0.2.…”

Section: Methodsmentioning

confidence: 99%

“…In recent years, a number of Syk inhibitors have been discovered for treatment of autoimmune, allergic and autoinflammatory diseases and most of them are ATP-competitive Syk inhibitors [ 3 , 10 , 11 , 12 ]. Several research groups have independently reported the crystal structures of the Syk catalytic domain, co-crystallized and ligand soaked with small molecule inhibitors [ 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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A Combined Experimental and Computational Study of Vam3, a Derivative of Resveratrol, and Syk Interaction

Jiang

Liu

Chen

et al. 2014

IJMS

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Spleen tyrosine kinase (Syk) plays an indispensable role through preliminary extracellular antigen-induced crosslinking of Fc receptor (FcR) in the pathogenesis of autoimmune disorders, such as rheumatoid arthritis. In this study, we identify Vam3, a dimeric derivative of resveratrol isolated from grapes, as an ATP-competitive inhibitor of Syk with an IC50 of 62.95 nM in an in vitro kinase assay. Moreover, docking and molecular dynamics simulation approaches were performed to get more detailed information about the binding mode of Vam3 and Syk. The results show that 11b-OH on ring-C and 4b-OH on ring-D could form two hydrogen bonds with Glu449 and Phe382 of Syk, respectively. In addition, arene-cation interaction between ring-D of Vam3 and Lys402 of Syk was also observed. These results indicate that ring-C and D play an essential role in Vam3–Syk interaction. Our studies may be helpful in the structural optimization of Vam3, and also aid the design of novel Syk inhibitors in the future.

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“…Pyridine nuclei constitute the core of a wide number of biologically active natural products9 and are important compounds that are widely employed in the fields of biochemistry, pharmaceuticals, and materials science 10. Aminopyridines11a have recently been used for neurological disorders,11b as Syk kinase inhibitors,11c and for metal‐catalyzed C–H and C–C bond activation 11d. In this context, the development of new methods for the preparation of fluorine‐substituted heterocycles is an interesting goal of synthetic organic chemistry, not only for their use in medicinal chemistry4 but also for the development of active ingredients for crop protection5 and materials 6…”

Section: Introductionmentioning

confidence: 99%

Regioselective Conjugate Addition of Nitriles to α,β‐Unsaturated Imines: Synthesis of Fluorinated Primary Enamines and 2‐Aminopyridine Derivatives

Trocóniz¹,

Retana²,

Pascual³

et al. 2013

Eur J Org Chem

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The regioselective Michael addition of the carbanion of 2‐phenylacetonitrile (R2 = Ph) and malononitrile (R2 = CN) to fluoroalkylated α,β‐unsaturated imines 1 is described. Fluorinated imines 1 were used as intermediates for the regioselective 1,4‐addition and synthesis of functionalized fluorinated primary enamines 5 and 7, fluorine‐containing trans‐3,4‐dihydro‐2‐aminopyridines 2, and fluorinated 2‐aminopyridines 4 and 8, which were obtained with total atom economy. Derivatives 2 and 8 were also prepared by an intramolecular cyclocondensation reaction of functionalized fluorinated primary enamines 5 and 7, respectively, in the presence of a base (NaH).

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Highly potent aminopyridines as Syk kinase inhibitors

Cited by 20 publications

References 10 publications

Solution structure of a pentachromium(ii) single molecule magnet from DFT calculations, isotopic labelling and multinuclear NMR spectroscopy

Solution structure of a pentachromium(ii) single molecule magnet from DFT calculations, isotopic labelling and multinuclear NMR spectroscopy

A Combined Experimental and Computational Study of Vam3, a Derivative of Resveratrol, and Syk Interaction

Regioselective Conjugate Addition of Nitriles to α,β‐Unsaturated Imines: Synthesis of Fluorinated Primary Enamines and 2‐Aminopyridine Derivatives

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