ABSTRACT
We developed the first nickel-catalyzed direct ortho-thiolation of N-benzoyl α-amino acid derivatives. This novel strategy showed wide generality, functional tolerance, and high regioselectivity. In addition, dipeptide derivatives were also compatible with this transformation system, providing a potential protocol for the direct modification of peptide derivatives.
ABSTRACT
A series of novel 5-(benzyloxy)pyridin-2(1H)-ones were designed, synthesized and biologically evaluated for c-Met inhibition. Various amides and benzoimidazoles at C-3 position were investigated. A potent compound 12b with a c-Met IC50 of 12nM was identified. This compound exhibited potent inhibition of EBC-1 cell associated with c-Met constitutive activation and showed high selectivity for c-Met than other tested 11 kinases. The binding model 12b with c-Met was disclosed by docking analysis.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridones/chemistry , Pyridones/pharmacology , Cell Line, Tumor , Drug Design , Humans , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-met/chemistry , Pyridones/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC50 up to 7.7nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71µM) and c-Met activation-mediated cell metastasis. At a dose of 100mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Dogs , Drug Resistance, Neoplasm/drug effects , Half-Life , Humans , Madin Darby Canine Kidney Cells , Mice , Mice, Nude , Molecular Docking Simulation , NIH 3T3 Cells , Neoplasms/drug therapy , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/toxicity , Protein Structure, Tertiary , Proto-Oncogene Proteins c-met/metabolism , Pyridines/pharmacokinetics , Pyridines/toxicity , Rats , Signal Transduction/drug effects , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonamides/toxicity , Transplantation, HeterologousABSTRACT
A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the scaffold was explored. In this study, a promising compound (S)-24o with a c-Met IC(50) of 0.022 µM was identified. The compound exhibited dose-dependent inhibition of the phosphorylation of c-Met as well as downstream signaling in EBC-1 cells. Furthermore, the interactive binding model of (S)-24o with c-Met was elucidated by virtue of a molecular modeling study.
Subject(s)
Aminopyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Discovery , Niacinamide/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Aminopyridines/chemical synthesis , Aminopyridines/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/pharmacology , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/metabolism , Structure-Activity RelationshipABSTRACT
A series of N'-(2-oxoindolin-3-ylidene)hydrazide derivatives were identified as moderately potent inhibitors against c-Met kinase by pharmacophore-based virtual screening and chemical synthesis methods. The structure-activity relationship (SAR) at various positions of the scaffold was investigated and its binding mode with c-Met kinase was analyzed by molecular modeling studies. In this study, two potent compounds D2 and D25, with IC(50) value at 1.3 µM and 2.2 µM against c-Met kinase respectively, were identified. Finally, based on the clues extracted from this study, future development for the optimization of this scaffold was discussed.
Subject(s)
Hydrazines/chemical synthesis , Indoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Binding Sites , Enzyme Activation/drug effects , Hydrazines/chemistry , Hydrazines/pharmacology , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A novel and efficient process for the synthesis of alpha-sialyl spirohydantoin analogues via one-pot sequential reaction involving various carbodiimides and peracetylated Neu5Ac is reported. BF(3) x Et(2)O mediating intramolecular N-sialylation with excellent alpha-selectivity is first demonstrated.
Subject(s)
Carbodiimides/chemistry , Hydantoins/chemical synthesis , Sialic Acids/chemistry , Acetylation , Organic Chemistry Phenomena , Spiro Compounds/chemistryABSTRACT
We have developed a simple method for the synthesis of pyrrolo/pyrido[2,1-a][1,3]benzoxazinones and pyrrolo/pyrido[2,1-a]quinazolinones from 2-amino benzoic acids and 2-amino benzamides via a gold(I)-catalyzed tandem coupling/cyclization process. The tricyclic or polycyclic molecular architectures were constructed in one pot with the formation of three new bonds.
Subject(s)
Benzoxazines/chemical synthesis , Gold/chemistry , Quinazolinones/chemical synthesis , Benzoxazines/chemistry , Catalysis , Molecular Structure , Quinazolinones/chemistry , StereoisomerismABSTRACT
An efficient approach to the dehydrative sialylation of various substrates with C-4-aminated sialyl-hemiketal donors by using the reagent combination of diphenyl sulfoxide and triflic anhydride is reported. By using a C-4-hindered non-nucleophilic amine auxiliary, excellent yields and high alpha-stereoselectivities were obtained for coupling with a wide range of primary and secondary acceptors.
Subject(s)
Amines/chemistry , Benzene Derivatives/chemistry , Mesylates/chemistry , N-Acetylneuraminic Acid/chemistry , Acetylation , Pyrimidines/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
The first site-specific and purely chemical method for modifying proline-based peptides was developed via a convenient, copper-catalyzed oxidative coupling of tertiary amine N-oxides with indoles. This novel approach features high regioselectivity and diastereoselectivity, mild conditions, and compatibility with various functional groups. In addition, a simplified process was realized in one pot and two steps via in situ oxidative coupling of tertiary amine and indoles.
Subject(s)
Copper/chemistry , Oxides/chemistry , Peptides/chemistry , Amines/chemistry , Catalysis , Indoles/chemistry , Oxidative Coupling , Proline/chemistry , StereoisomerismABSTRACT
An unprecedented palladium-catalyzed picolinamide-directed coupling of C(sp(2))-H and C(sp(2))-H has been developed with exclusive formation of the six-membered ring heterocyclics - quinolinone and pyridone. The method employs cyclic hypervalent iodine as oxidant and features good functional-group tolerance. Another advantage of this reaction is that sequential C-H/C-H and C-H/N-H coupling could be achieved.
ABSTRACT
A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC50 values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound 22e inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated cancer cells and model cells. Compound 22e significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different species has been proposed, and a major NADPH-dependent metabolite 33 was generated by liver microsomes. To block the metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaffold showed promising pharmacological inhibition of c-Met and warrants further investigation.
ABSTRACT
[This corrects the article DOI: 10.1021/ml4000047.].
ABSTRACT
A facile, copper-mediated, direct C-H(sp(2))/C-H(sp(3)) bond coupling of benzoic acid derivatives with ethyl cyanoacetate by the deployment of an 8-aminoquinoline moiety as a bidentate directing group is disclosed. Such a unique transformation provides a new strategy for the construction of an isoquinolinone scaffold as one of the privileged cores.
Subject(s)
Acetates/chemistry , Aminoquinolines/chemistry , Benzoic Acid/chemistry , Copper/chemistry , Carbon/chemistry , Catalysis , Coordination Complexes/chemistry , Hydrogen/chemistry , Oxidation-Reduction , Quantum TheoryABSTRACT
Palladium-catalyzed intramolecular addition of C-N and S-N bond to alkynes with the migration of functional groups has been achieved. A wide range of functional groups including acyl, pyruvoyl, amide, and sulfonyl groups can migrate smoothly and be conveniently introduced at the C-3 postion of indoles in our catalytic system. The operational simplicity and broad substrate scope demonstrate the great potential of this method for the synthesis of highly functional indoles.
Subject(s)
Alkynes/chemistry , Indoles/chemical synthesis , Palladium/chemistry , Catalysis , Cyclization , Indoles/chemistry , Molecular StructureABSTRACT
SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKK(ac)-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKK(ac)-AMC complex model based on the crystal structure. K(m) and K(d) determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through π-stacking, while the other portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators.
Subject(s)
Fluorescent Dyes/chemistry , Sirtuin 1/metabolism , Acetylation , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Sirtuin 1/chemistry , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
The aberrant function of c-Met kinase signaling pathway is ubiquitously involved in a broad spectrum of human cancers; thus, a strong rationale exists for targeting the kinase pathway in cancer therapy. Via integration of computational and experimental studies, anthraquinone derivatives were identified for the first time as potent c-Met kinase inhibitors in this research. The aberrant activation of the c-Met kinase pathway results from (TPR)-Met, MET gene mutation, or amplification and a hepatocyte growth factor (HGF)/scatter factor-dependent autocrine or paracrine mechanism. However, anthraquinone derivatives exclusively suppressed c-Met phosphorylation stimulated by HGF in A549 cells, indicating that the compounds possess the ability to block the extracellular HGF-dependent pathway. A surface plasmon resonance assay revealed that the most potent compound, 2a, shows a high binding affinity for HGF with an equilibrium dissociation constant of 1.95 µM. The dual roles of compound 2a demonstrate the potency of anthraquinone derivatives and provide a new design solution for the c-Met kinase signaling pathway.
ABSTRACT
A practical Pd(PPh(3))(4)/DBU catalytic system for the synthesis of pharmaceutically relevant aminopyridine nitrile intermediates, as well as a variety of other aryl nitriles using non-toxic K(4)[Fe(CN)(6)] has been developed. The key features of our new protocol for cyanation lie in that the reaction can be carried out with readily available Pd(PPh(3))(4) under mild and green conditions, even without the assistance of other ligands.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bromides/chemistry , Coordination Complexes/chemistry , Ferrocyanides/chemistry , Palladium/chemistry , Catalysis , Ligands , Nitriles/chemistryABSTRACT
The recent emergence of the highly pathogenic H5N1 subtype of avian influenza virus (AIV) and of the new type of human influenza A (H1N1) have emphasized the need for the development of effective anti-influenza drugs. Presently, neuraminidase (NA) inhibitors are widely used in the treatment and prophylaxis of human influenza virus infection, and tremendous efforts have been made to develop more potent NA inhibitors to combat resistance and new influenza viruses. In this review, we discuss the structural characteristics of NA catalytic domains and the recent developments of new NA inhibitors using structure-based drug design strategies. These drugs include analogues of zanamivir, analogues of oseltamivir, analogues of peramivir, and analogues of aromatic carboxylic acid and present promising options for therapeutics or leads for further development of NA inhibitors that may be useful in the event of a future influenza pandemic.