ABSTRACT
Introduction of a 1-benzyl-1H-pyrazol-4-yl moiety at C7 of the imidazo[4,5-b]pyridine scaffold provided 7a which inhibited a range of kinases including Aurora-A. Modification of the benzyl group in 7a, and subsequent co-crystallisation of the resulting analogues with Aurora-A indicated distinct differences in binding mode dependent upon the pyrazole N-substituent. Compounds 7a and 14d interact with the P-loop whereas 14a and 14b engage with Thr217 in the post-hinge region. These crystallographic insights provide options for the design of compounds interacting with the DFG motif or with Thr217.
Subject(s)
Aurora Kinases/antagonists & inhibitors , Aurora Kinases/chemistry , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallization , Dose-Response Relationship, Drug , Humans , Imidazoles/chemistry , Mice , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Binding Sites , Crystallography, X-Ray , Kinetics , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.
Subject(s)
Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Drug Design , Imidazoles/chemistry , Imidazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Aurora Kinase A/chemistry , Aurora Kinase A/metabolism , Aurora Kinase B/chemistry , Aurora Kinase B/metabolism , Catalytic Domain , Drug Stability , HCT116 Cells , Humans , Imidazoles/metabolism , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Isoenzymes/metabolism , Male , Mice , Molecular Docking Simulation , Protein Kinase Inhibitors/metabolism , Substrate SpecificityABSTRACT
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Benzothiazoles/chemical synthesis , Crystallography, X-Ray , Drug Design , Humans , Mice , Models, Molecular , Protein-Tyrosine Kinases/chemistry , Signal Transduction , Structure-Activity RelationshipABSTRACT
A practically simple three-component Strecker reaction for the asymmetric synthesis of enantiopure α-arylglycines has been developed. Addition of a range of aryl-aldehydes to a solution of sodium cyanide and (S)-1-(4-methoxyphenyl)ethylamine affords highly crystalline (S,S)-α-aminonitriles that are easily obtained in diastereomerically pure form. Heating the resultant (S,S)-α-aminonitriles in 6 M aqueous HCl at reflux resulted in cleavage of their chiral auxiliary fragments and concomitant hydrolysis of their nitrile groups to afford enantiopure (S)-α-arylglycines. The enantiopurities of these (S)-α-arylglycines were determined via derivatization of their corresponding methyl esters with 2-formylphenylboronic acid and (S)-BINOL, followed by (1)H NMR spectroscopic analysis of the resultant mixtures of diastereomeric iminoboronate esters.
Subject(s)
Benzaldehydes/chemistry , Boronic Acids/chemistry , Glycine/chemistry , Glycine/chemical synthesis , Esters , Glycine/analogs & derivatives , Hydrolysis , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Ring-closing metathesis was used to construct the strained 11-membered ring of obtusallenes II (and IV). Bromonium ion induced transannular oxonium ion formation-fragmentation gave the macrocyclic carbon skeleton of obtusallene VII with a bromine atom at C-13, in line with a previously published hypothesis. An additional brominated [5.5.1]bicyclotridecane adduct that must arise from a bromonium ion induced transannular oxonium ion formation-fragmentation could also be isolated, suggesting that this adduct represents the core of an as yet undiscovered natural product. An authentic sample of obtusallene V was studied by NMR spectroscopy, and the position of the halogens at C-7 and C-13 was reassigned on the basis of a (13)C NMR chlorine induced isotopic shift. This revised structure was subsequently confirmed by X-ray crystallography. These findings allow us to confidently conclude that the structures of obtusallenes VII and VI should also be reassigned.
Subject(s)
Bromine/chemistry , Ethers, Cyclic/chemistry , Oxygen/chemistry , Cyclization , Ethers, Cyclic/chemical synthesis , Ions/chemistry , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
Enynes undergo stereoselective syn intramolecular bromoetherification; the stereochemical course of the reaction was elucidated by X-ray crystallographic studies and by stereospecific synthesis of authentic bromoallenes.
Subject(s)
Alkadienes/chemical synthesis , Alkynes/chemistry , Hydrocarbons, Brominated/chemical synthesis , Alkadienes/chemistry , Hydrocarbons, Brominated/chemistry , Molecular Conformation , StereoisomerismABSTRACT
A simple three-component chiral derivatization protocol for determining the enantiopurity of chiral primary amines by 1H NMR spectroscopic analysis is described here. The method involves condensation of the amines with 2-formylphenylboronic acid and enantiopure 1,1'-bi-2-naphthol. This approach affords a mixture of diastereoisomeric iminoboronate esters whose ratio can be determined by the integration of well-resolved diastereotopic resonances in their 1H NMR spectra, thus enabling the enantiopurity of the parent amine to be determined easily. The protocol, as described, takes less than 90 min to complete.
Subject(s)
Amines/chemistry , Magnetic Resonance Spectroscopy/methods , Amines/analysis , Amines/metabolism , Benzaldehydes/chemistry , Benzylamines/chemistry , Benzylamines/metabolism , Boronic Acids/chemistry , Esters/chemistry , Molecular Structure , Naphthols/chemistryABSTRACT
A three-component chiral derivatization protocol for determining the enantiopurity of chiral diols by (1)H NMR spectroscopic analysis is described here. The present approach involves the derivatization of 1,2- 1,3- and 1,4-diols with 2-formylphenylboronic acid and enantiopure alpha-methylbenzylamine. This method affords a mixture of diastereoisomeric iminoboronate esters whose ratio can be determined by integration of well-resolved diastereotopic resonances in their (1)H NMR spectra, thus enabling the determination of the enantiopurity of the parent diol. The protocol as described takes less than 90 min to complete.
Subject(s)
Alcohols/chemistry , Magnetic Resonance Spectroscopy/methods , Alcohols/metabolism , Benzaldehydes/chemistry , Benzylamines/chemistry , Boronic Acids/chemistry , Esters/chemistry , Molecular Structure , Phenethylamines/chemistry , StereoisomerismABSTRACT
[reaction: see text] Sharpless asymmetric dihydroxylation was regioselective for the trans olefin in an E vs Z vs terminal triene substrate. To test a biosynthetic hypothesis, the resulting diol underwent diastereoselective bromoetherification to provide the des-chloro core of marine natural products obtusallenes II and IV. Alternatively, anionic chloride ring-opening of a Z-beta,gamma-unsaturated epoxide gave separable regioisomeric halohydrins. Bromoetherification gave the fully elaborated core of obtusallenes II and IV with all of the relative stereochemistry correctly set.
Subject(s)
Biological Products/chemistry , Furans/chemical synthesis , Laurencia/chemistry , Marine Biology , Bromine/chemistry , Epoxy Compounds/chemistry , Ethers/chemistry , Hydroxylation , Models, Chemical , StereoisomerismABSTRACT
[reaction: see text] A practically simple three-component chiral derivatization protocol for determining the enantiopurity of chiral 1,2-, 1,3-, and 1,4-diols by (1)H NMR spectroscopic analysis is described. The method involves treatment with 2-formylphenylboronic acid and enantiopure alpha-methylbenzylamine to afford a mixture of diastereoisomeric iminoboronate esters whose ratio is an accurate reflection of the enantiopurity of the parent diol.
ABSTRACT
[reaction: see text] A practically simple three-component chiral derivatizing protocol for determining the enantiopurity of 13 chiral primary amines by (1)H NMR spectroscopic analysis is described, including analysis of those that contain remote stereocenters.
