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1.
Am J Physiol Lung Cell Mol Physiol ; 325(6): L726-L740, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37847710

RESUMO

Common respiratory diseases continue to represent a major public health problem, and much of the morbidity and mortality is due to airway inflammation and mucus production. Previous studies indicated a role for mitogen-activated protein kinase 14 (MAPK14) in this type of disease, but clinical trials are unsuccessful to date. Our previous work identified a related but distinct kinase known as MAPK13 that is activated in respiratory airway diseases and is required for mucus production in human cell-culture models. Support for MAPK13 function in these models came from effectiveness of MAPK13 versus MAPK14 gene-knockdown and from first-generation MAPK13-14 inhibitors. However, these first-generation inhibitors were incompletely optimized for blocking activity and were untested in vivo. Here we report the next generation and selection of a potent MAPK13-14 inhibitor (designated NuP-3) that more effectively downregulates type-2 cytokine-stimulated mucus production in air-liquid interface and organoid cultures of human airway epithelial cells. We also show that NuP-3 treatment prevents respiratory airway inflammation and mucus production in new minipig models of airway disease triggered by type-2 cytokine challenge or respiratory viral infection. The results thereby provide the next advance in developing a small-molecule kinase inhibitor to address key features of respiratory disease.NEW & NOTEWORTHY This study describes the discovery of a potent mitogen-activated protein kinase 13-14 (MAPK13-14) inhibitor and its effectiveness in models of respiratory airway disease. The findings thereby provide a scheme for pathogenesis and therapy of lung diseases [e.g., asthma, chronic obstructive pulmonary disease (COPD), Covid-19, postviral, and allergic respiratory disease] and related conditions that implicate MAPK13-14 function. The findings also refine a hypothesis for epithelial and immune cell functions in respiratory disease that features MAPK13 as a possible component of this disease process.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Doença Pulmonar Obstrutiva Crônica , Animais , Humanos , Suínos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Porco Miniatura/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Muco/metabolismo , Citocinas/metabolismo , Proteína Quinase 13 Ativada por Mitógeno/metabolismo
2.
bioRxiv ; 2023 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-37292761

RESUMO

Common respiratory diseases continue to represent a major public health problem, and much of the morbidity and mortality is due to airway inflammation and mucus production. Previous studies indicated a role for mitogen-activated protein kinase 14 (MAPK14) in this type of disease, but clinical trials are unsuccessful to date. Our previous work identified a related but distinct kinase known as MAPK13 that is activated in respiratory airway diseases and is required for mucus production in human cell-culture models. Support for MAPK13 function in these models came from effectiveness of MAPK13 versus MAPK14 gene-knockdown and from first-generation MAPK13-14 inhibitors. However, these first-generation inhibitors were incompletely optimized for blocking activity and were untested in vivo. Here we report the next generation and selection of a potent MAPK13-14 inhibitor (designated NuP-3) that more effectively down-regulates type-2 cytokine-stimulated mucus production in air-liquid interface and organoid cultures of human airway epithelial cells. We also show that NuP-3 treatment prevents respiratory airway inflammation and mucus production in new minipig models of airway disease triggered by type-2 cytokine challenge or respiratory viral infection. The results thereby provide the next advance in developing a small-molecule kinase inhibitor to address key features of respiratory disease.

3.
J Med Chem ; 62(2): 480-490, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30571119

RESUMO

Matriptase and hepsin belong to the family of type II transmembrane serine proteases (TTSPs). Increased activity of these and the plasma protease, hepatocyte growth factor activator (HGFA), is associated with unregulated cell signaling and tumor progression through increased MET and RON kinase signaling pathways. These proteases are highly expressed in multiple solid tumors and hematological malignancies. Herein, we detail the synthesis and structure-activity relationships (SAR) of a dipeptide library bearing Arg α-ketobenozothiazole (kbt) warheads as novel inhibitors of HGFA, matriptase, and hepsin. We elucidated the substrate specificity for HGFA using positional scanning of substrate combinatorial libraries (PS-SCL), which was used to discover selective inhibitors of matriptase and hepsin. Using these selective inhibitors, we have clarified the specific role of hepsin in maintaining epithelial cell membrane integrity, known to be lost in breast cancer progression. These selective compounds are useful as chemical biology tools and for future drug discovery efforts.


Assuntos
Serina Endopeptidases/química , Inibidores de Serina Proteinase/química , Sítios de Ligação , Linhagem Celular Tumoral , Dipeptídeos/química , Dipeptídeos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato
4.
Oncotarget ; 8(38): 63014-63025, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28968967

RESUMO

Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment. The tumor microenvironment plays a major role in resistance to anticancer therapy. We demonstrated that fibroblasts block the response of MET-amplified NSCLC cells to the MET kinase inhibitor, JNJ38877605 in an HGF-dependent manner. Thus, MET-amplified NSCLC cells become addicted to HGF upon pharmacological inhibition of MET. HGF restored phosphorylation of MET, EGFR and RON, and maintained pro-survival AKT and ERK signaling in MET-inhibited cells. We developed a small molecule inhibitor of pro-HGF activation, SRI31215, which acts as a triplex inhibitor of the pro-HGF activating proteases matriptase, hepsin and HGF activator (HGFA). SRI31215 blocked crosstalk between tumor cells and fibroblasts and overcame fibroblast-mediated resistance to MET inhibition by preventing fibroblast-mediated reactivation of AKT and ERK signaling. Structurally unrelated triplex inhibitors of matriptase, hepsin and HGFA that we developed in parallel showed similar biological activity. Our data suggest that simultaneous inhibition of HGF and MET is required to overcome resistance to MET inhibitors in MET-amplified NSCLC cells. This provides a rationale for the development of novel combination therapeutic strategies for the treatment of NSCLC patients with MET amplification.

5.
J Med Chem ; 59(20): 9390-9408, 2016 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-27689912

RESUMO

Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Manosídeos/administração & dosagem , Manosídeos/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Relação Dose-Resposta a Droga , Feminino , Manosídeos/química , Camundongos , Camundongos Endogâmicos C3H , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Virulência/efeitos dos fármacos
6.
ChemMedChem ; 11(6): 585-99, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26889658

RESUMO

Upregulation of the HGF and MSP growth-factor processing serine endopeptidases HGFA, matriptase and hepsin is correlated with increased metastasis in multiple tumor types driven by c-MET or RON kinase signaling. We rationally designed P1' α-ketobenzothiazole mechanism-based inhibitors of these proteases. Structure-activity studies are presented, which resulted in the identification of potent inhibitors with differential selectivity. The tetrapeptide inhibitors span the P1-P1' substrate cleavage site via a P1' amide linker off the benzothiazole, occupying the S3' pocket. Optimized inhibitors display sub-nanomolar enzyme inhibition against one, two, or all three of HGFA, matriptase, and hepsin. Several compounds also have good selectivity against the related trypsin-like proteases, thrombin and Factor Xa. Finally, we show that inhibitors block the fibroblast (HGF)-mediated migration of invasive DU145 prostate cancer cells. In addition to prostate cancer, breast, colon, lung, pancreas, gliomas, and multiple myeloma tumors all depend on HGF and MSP for tumor survival and progression. Therefore, these unique inhibitors have potential as new therapeutics for a diverse set of tumor types.


Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Oligopeptídeos/farmacologia , Inibidores de Serina Proteinase/farmacologia , Antineoplásicos/síntese química , Benzotiazóis/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fator Xa/metabolismo , Humanos , Modelos Moleculares , Oligopeptídeos/síntese química , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/síntese química , Transdução de Sinais , Relação Estrutura-Atividade , Trombina/metabolismo
7.
ChemMedChem ; 11(4): 367-73, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26812660

RESUMO

Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ray structure of lead mannosides and then designed mannosides with improved drug-like properties. We show that cyclizing the carboxamide onto the biphenyl B-ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2-methyl-4-(1-oxo-1,2-dihydroisoquinolin-7-yl)phenyl α-d-mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N-Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22, as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria-mediated hemagglutination and prevent biofilm formation by UPEC with single-digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.


Assuntos
Adesinas de Escherichia coli/metabolismo , Antibacterianos/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Proteínas de Fímbrias/metabolismo , Manosídeos/farmacologia , Infecções Urinárias/tratamento farmacológico , Escherichia coli Uropatogênica/efeitos dos fármacos , Antibacterianos/química , Doença Crônica , Infecções por Escherichia coli/microbiologia , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Manosídeos/química , Simulação de Acoplamento Molecular , Bexiga Urinária/microbiologia , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/metabolismo
8.
Bioorg Med Chem ; 23(10): 2328-43, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25882520

RESUMO

Hepatocyte growth factor activator (HGFA), matriptase and hepsin are all S1 trypsin-like serine endopeptidases. HGFA is a plasma protease while hepsin and matriptase are type II transmembrane proteases (TTSPs). Upregulated expression and activity of all three proteases is associated with aberrant cancer cell signaling through c-MET and RON tyrosine kinase cell-signaling pathways in cancer. We modeled known benzamidine protease inhibitor scaffolds into the active sites of matriptase, hepsin and HGFA to design new non-peptide inhibitors of hepsin and HGFA. First, we used a docking model of the irreversible inhibitor, Nafamostat, bound to the active site of HGFA in order to explore structure activity relationships (SAR). Compounds were screened for inhibition of HGFA activity in a kinetic enzyme assay using a chromogenic substrate. Next, we designed matched pair compound libraries of 3-amidino and 4-amidino phenylalanine (benzamidine) arginine peptidomimetics based on the structure of matriptase inhibitor, CJ-672. Compounds were screened for inhibition of HGFA, matriptase, and hepsin enzyme activity using fluorogenic substrates. Using this strategy we have discovered the first reported non-peptide small molecule inhibitors of both HGFA and hepsin. These inhibitors have differential potency and selectivity towards all three proteases. A subset of piperazinyl ureas highlighted by 25a, have excellent potency and selectivity for hepsin over matriptase and HGFA.


Assuntos
Antineoplásicos/síntese química , Benzamidinas/síntese química , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteases/síntese química , Serina Endopeptidases/química , Amidinas/síntese química , Antineoplásicos/farmacologia , Arginina/química , Benzamidinas/farmacologia , Domínio Catalítico , Desenho de Fármacos , Ensaios Enzimáticos , Guanidinas/química , Ensaios de Triagem em Larga Escala , Humanos , Cinética , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/química , Peptidomiméticos/química , Fenilalanina/análogos & derivados , Fenilalanina/síntese química , Piperazinas/síntese química , Inibidores de Proteases/farmacologia , Proteínas Recombinantes/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
9.
ACS Med Chem Lett ; 5(11): 1219-24, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25408834

RESUMO

Hepatocyte growth factor activators (HGFA), matriptase, and hepsin are S1 family trypsin-like serine proteases. These proteases proteolytically cleave the single-chain zymogen precursors, pro-HGF (hepatocyte growth factor), and pro-MSP (macrophage stimulating protein) into active heterodimeric forms. HGF and MSP are activating ligands for the oncogenic receptor tyrosine kinases (RTKs), c-MET and RON, respectively. We have discovered the first substrate-based ketothiazole inhibitors of HGFA, matriptase and hepsin. The compounds were synthesized using a combination of solution and solid-phase peptide synthesis (SPPS). Compounds were tested for protease inhibition using a kinetic enzyme assay employing fluorogenic peptide substrates. Highlighted HGFA inhibitors are Ac-KRLR-kt (5g), Ac-SKFR-kt (6c), and Ac-SWLR-kt (6g) with K is = 12, 57, and 63 nM, respectively. We demonstrated that inhibitors block the conversion of native pro-HGF and pro-MSP by HGFA with equivalent potency. Finally, we show that inhibition causes a dose-dependent decrease of c-MET signaling in MDA-MB-231 breast cancer cells. This preliminary investigation provides evidence that HGFA is a promising therapeutic target in breast cancer and other tumor types driven by c-MET and RON.

10.
Antimicrob Agents Chemother ; 56(9): 4738-45, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22733070

RESUMO

Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract. We report that these biological perturbations impact UPEC pathogenesis and that bacterial reservoirs established during a previous UPEC infection, in which bacteriuria had resolved, can serve as a nidus for subsequent urinary catheter colonization. Mannosides, small molecule inhibitors of the type 1 pilus adhesin, FimH, provided significant protection against UPEC CAUTI by preventing bacterial invasion and shifting the UPEC niche primarily to the extracellular milieu and on the foreign body. By doing so, mannosides potentiated the action of trimethoprim-sulfamethoxazole in the prevention and treatment of CAUTI. In this study, we provide novel insights into UPEC pathogenesis in the context of urinary catheterization, and demonstrate the efficacy of novel therapies that target critical mechanisms for this infection. Thus, we establish a proof-of-principle for the development of mannosides to prevent and eventually treat these infections in the face of rising antibiotic-resistant uropathogens.


Assuntos
Infecções Relacionadas a Cateter/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Infecções por Escherichia coli/tratamento farmacológico , Manosídeos/farmacologia , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Infecções Urinárias/tratamento farmacológico , Escherichia coli Uropatogênica/efeitos dos fármacos , Adesinas de Escherichia coli/genética , Animais , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Infecções Relacionadas a Cateter/microbiologia , Infecção Hospitalar/microbiologia , Quimioterapia Combinada , Infecções por Escherichia coli/microbiologia , Feminino , Proteínas de Fímbrias/deficiência , Proteínas de Fímbrias/genética , Deleção de Genes , Manosídeos/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/microbiologia , Cateteres Urinários/microbiologia , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/crescimento & desenvolvimento , Escherichia coli Uropatogênica/patogenicidade
11.
J Med Chem ; 55(8): 3945-59, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22449031

RESUMO

Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve druglike physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements several-fold higher than those of corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or "tyrosine gate" (Tyr137 and Tyr48) also lined by Ile52. The lead mannosides have increased metabolic stability and oral bioavailability as determined from in vitro PAMPA predictive model of cellular permeability and in vivo pharmacokinetic studies in mice, thereby representing advanced preclinical candidates with promising potential as novel therapeutics for the clinical treatment and prevention of recurring urinary tract infections.


Assuntos
Compostos de Bifenilo/farmacologia , Proteínas de Fímbrias/antagonistas & inibidores , Manosídeos/farmacologia , Adesinas de Escherichia coli , Animais , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacocinética , Testes de Inibição da Hemaglutinação , Manosídeos/síntese química , Manosídeos/química , Manosídeos/farmacocinética , Camundongos , Relação Estrutura-Atividade , Infecções Urinárias
12.
Sci Transl Med ; 3(109): 109ra115, 2011 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-22089451

RESUMO

Chronic and recurrent urinary tract infections pose a serious medical problem because there are few effective treatment options. Patients with chronic urinary tract infections are commonly treated with long-term prophylactic antibiotics that promote the development of antibiotic-resistant forms of uropathogenic Escherichia coli (UPEC), further complicating treatment. We developed small-molecular weight compounds termed mannosides that specifically inhibit the FimH type 1 pilus lectin of UPEC, which mediates bacterial colonization, invasion, and formation of recalcitrant intracellular bacterial communities in the bladder epithelium. Here, we optimized these compounds for oral bioavailability and demonstrated their fast-acting efficacy in treating chronic urinary tract infections in a preclinical murine model. These compounds also prevented infection in vivo when given prophylactically and strongly potentiated the activity of the current standard of care therapy, trimethoprim-sulfamethoxazole, against clinically resistant PBC-1 UPEC bacteria. These compounds have therapeutic efficacy after oral administration for the treatment of established urinary tract infections in vivo. Their unique mechanism of action-targeting the pilus tip adhesin FimH-circumvents the conventional requirement for drug penetration of the outer membrane, minimizing the potential for the development of resistance. The small-molecular weight compounds described herein promise to provide substantial benefit to women suffering from chronic and recurrent urinary tract infections.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Proteínas de Fímbrias/antagonistas & inibidores , Infecções Urinárias/tratamento farmacológico , Escherichia coli Uropatogênica/patogenicidade , Adesinas de Escherichia coli , Animais , Antibacterianos/síntese química , Antibacterianos/química , Feminino , Espectroscopia de Ressonância Magnética , Manosídeos/síntese química , Manosídeos/química , Manosídeos/farmacocinética , Manosídeos/uso terapêutico , Camundongos , Microscopia Confocal , Estrutura Molecular , Escherichia coli Uropatogênica/efeitos dos fármacos
13.
J Med Chem ; 53(12): 4779-92, 2010 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-20507142

RESUMO

FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on alpha-d-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biarylmannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and submicromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including pi-pi interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt bridge. Dimeric analogues linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections.


Assuntos
Antibacterianos/síntese química , Proteínas de Fímbrias/antagonistas & inibidores , Manosídeos/síntese química , Adesinas de Escherichia coli , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Ligação Competitiva , Cristalografia por Raios X , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Polarização de Fluorescência , Cobaias , Testes de Hemaglutinação , Ligação de Hidrogênio , Manosídeos/química , Manosídeos/farmacologia , Modelos Moleculares , Ligação Proteica , Relação Estrutura-Atividade
14.
J Org Chem ; 73(2): 445-50, 2008 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-18085793

RESUMO

The cobalt-catalyzed cyclotrimerization of bis(4-pyridyl)acetylene affords hexakis(4-pyridyl)benzene in moderate yield. Alkylation with n-butyltriflate gives hexakis(4-(N-butylpyridylium))benzene triflate (1 6+), which can be reduced with Na/Hg in DMF to neutral 10. A single-crystal X-ray diffraction structure reveals that 1 0 has a chair-cyclohexane-like core and a [6]radialene structure. Cyclic voltammetry shows that 1 6+ is reversibly reduced to 1 2+ in one four-electron step and 1 2+ is reversibly reduced to 1 0 in one two-electron step. A reduction by four electrons at one potential is unprecedented for a molecule in which the electrochemically active centers are in electronic communication. The large structural transformation from 1 6+ to 1 0 is responsible for the "potential inversion" in the cyclic voltammetry, and DFT calculations suggest a possible structure for the stable intermediate 1 2+. A comparison is made to the electrochemistry and structural transformations in a previously prepared [4]radialene analogue of 1 0.


Assuntos
Derivados de Benzeno/química , Compostos de Piridínio/química , Derivados de Benzeno/síntese química , Cristalografia por Raios X , Ciclização , Eletroquímica , Elétrons , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Oxirredução , Compostos de Piridínio/síntese química
15.
Org Lett ; 9(1): 37-40, 2007 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-17192079

RESUMO

[reaction: see text] Catalytic activity of nonaromatic bicyclic amidines and bicyclic isothioureas in acylation reactions was found to be remarkably dependent on the sizes of both rings. DBN and especially its thia-analogue (THTP) have been identified as highly active acylation catalysts.


Assuntos
Amidinas/química , Acilação , Álcoois/química , Catálise , Ciclização , Estrutura Molecular
16.
Org Biomol Chem ; 3(9): 1622-3, 2005 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-15858641

RESUMO

Treatment of alpha, beta-unsaturated carbonyl compounds or methyl propargyl ether with acylchlorobis(cyclopentadienyl)titanium in the presence of triethylamine and a copper salt in aqueous THF resulted in acylation of the carbon-carbon multiple bond, yielding the corresponding 1,4-diketones in good yields.

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