Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.938
Filtrar
1.
Chemistry ; 26(22): 5070-5074, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32043659

RESUMO

Cγ -substituted proline derivatives are valuable tools for developing functionalized collagen peptides for biological and materials investigations, yet the stereochemistry at Cγ can produce undesired steric or stereoelectronic constraints. Alkylated γ-azaproline (γ-azPro) derivatives are proline mimetics that lack a stereogenic center at the γ-position of the ring and can thus utilize the invertibility of nitrogen to adapt their conformation. NMR spectroscopic analyses and DFT calculations highlighted how alkylated γ-azPro derivatives are conformationally dynamic and adopt conformational preferences through ring pucker flip along with nitrogen inversion. Lastly, incorporation of alkylated γ-azPro into collagen peptides produced functionalized pH-responsive triple helices with similar thermal stabilities, regardless of their placement in the Xaa or Yaa position within the characteristic Xaa-Yaa-Gly repeating unit of collagen peptides.


Assuntos
Compostos Aza/química , Colágeno/química , Peptídeos/química , Prolina/química , Alquilação , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética
2.
Chemphyschem ; 21(4): 307-312, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-31895487

RESUMO

Aza-o-quinone methides and their conjugated acids are reactive drug metabolites that might react with nucleophilic sites of DNAs and proteins to cause cancer or immune responses, and their reactivity with water is the key information to judge if these metabolites are harmful in living systems. For the first time, aza-o-quinone methide (1) and its conjugated acid (2) are observed by laser flash photolysis, and their reactivity, stability and acidity in water are determined.


Assuntos
Compostos Aza/química , Indolquinonas/química , Teoria da Densidade Funcional , Concentração de Íons de Hidrogênio , Estrutura Molecular , Fotólise , Água/química
3.
Chem Rec ; 20(2): 120-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31250972

RESUMO

Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N-heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine-containing saturated N-heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine-containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.


Assuntos
Compostos Aza/química , Compostos Heterocíclicos/química , Aldeídos/química , Azepinas/síntese química , Azepinas/química , Ciclização , Flúor/química , Compostos Heterocíclicos/síntese química , Oxirredução , Estereoisomerismo
4.
Bull Environ Contam Toxicol ; 104(1): 149-155, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31784766

RESUMO

This study was intended to develop an environment-friendly controlled release system for spirotetramat in an alginate matrix. Four formulations, starch-chitosan-calcium alginate (SCCA), starch-calcium alginate (SCA), chitosan-calcium alginate (CCA), and calcium alginate (CA) complex gel beads, were prepared by the extrusion-exogenous gelation method. The properties of the formulations were studied. The results showed that the release behaviors of the formulations in water could be well described by the logistic model, and the release occurred through Fickian diffusion. Among the four formulations, SCCA showed the highest entrapment efficiency, drug loading and the slowest release rate. Degradation studies revealed that the SCCA formulation exhibited an obvious slower degradation rate of spirotetramat in soils than the commercially available formulation. The estimated half-life of the SCCA formulation was 2.31, 3.25, and 4.51 days in waterloggogenic paddy soil, purplish soil, and montmorillonite, respectively, when the soils were moistened to 60% of its dry weight. This study provided a possible approach to prolong the duration of spirotetramat and to reduce environmental contamination.


Assuntos
Alginatos/química , Compostos Aza/química , Quitosana/química , Compostos de Espiro/química , Bentonita , Preparações de Ação Retardada , Ácido Glucurônico , Ácidos Hexurônicos , Amido
5.
J Pharm Biomed Anal ; 178: 112900, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31629973

RESUMO

PURPOSE: Gabapentin is degraded directly into a high toxicity form known as gabapentin lactam (gaba-L) with a maximizing desire in mild pH and low humidity. This study reports the lactamization process of gabapentin, along with a detailed analysis of the energy landscape, geometry, and thermodynamic and kinetic preference of the process. To investigate the effect of the acidic/basic conditions on the energy landscape, the energy profiles were investigated for both protonation and deprotonation forms of gabapentin. METHODS: All the calculations were performed by using the density functional theory (DFT) and the G4MP2 levels of theory in the conductor-like polarizable continuum model, CPCM, and water as the solvent. RESULTS: The lactamization process is an intramolecular cyclization which results in formation of gabapentin-lactam. The chemically intact gabapentin exists in two forms of a stable, R, and a relatively disordered form, R*. The conversion of stable crystalline form R to the intact unstable isomer R* is considered as the primary step in the gabapentin degradation. The results exhibited that near the unstable geometry, R*, a transition state (TS), is 41.3 kcal/mol higher in energy than the optimized ground state, R* (4.1 kcal/mol). From the intrinsic reaction coordinates (IRC) computations, it can be concluded that this transition state led to the unstable R* in one direction and to gabapentin-lactam in the other. CONCLUSIONS: The thermodynamic stability of the lactam form (-13.63 kcal/mol) clarifies the more thermal stability of gaba-L than its related gabapentin form and the experimental preference for the lactamization. The corresponding energy profile on protonation/deprotonation forms of gabapentin indicates the pH-dependent of the process and the rate reduction in out of the mild pH.


Assuntos
Analgésicos/química , Compostos Aza/química , Gabapentina/química , Modelos Teóricos , Compostos de Espiro/química , Cristalização , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Isomerismo , Solventes/química , Termodinâmica , Água/química
6.
Chem Pharm Bull (Tokyo) ; 67(10): 1123-1130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582632

RESUMO

The adenosine triphosphate derivatives of 2-oxo-1,3-diazaphenoxazine (dAdapTP) showed a significant discrimination ability for the template strand including that between 8-oxo-2'-deoxyguanosine (8-oxodG) and 2'-deoxyguanosine (dG) by the single nucleotide primer extension reaction using the Klenow Fragment. In this study, we synthesized new dAdapTP derivatives, i.e., 2-amino-dAdapTP, 2-chloro-dAdapTP and 2-iodo-dAdapTP, to investigate the effect on the selectivity and efficiency of incorporation for the primer extension reaction using a variety of DNA polymerases. In contrast to the previously tested dAdapTP, the selectivity and efficiency of the 2-halo-dAdapTP incorporation were dramatically decreased using the Klenow Fragment. Moreover, the efficiency of the 2-amino-dAdapTP incorporation into the T-containing template was almost the same with that of dAdapTP. In the case of the Bsu DNA polymerase, the efficiency of all the dAdapTP derivatives decreased compared to that using the Klenow Fragment. However, the incorporation selectivity of dAdapTP had improved against the oxodG-containing template for all the template sequences including the T-containing template. Moreover, 2-amino-dAdapTP showed a better efficiency than dAdapTP using the Bsu DNA polymerase. The 2-amino group of the adenosine unit may interact with syn-oxodG at the active site of the Bsu DNA polymerase during the single primer extension reaction.


Assuntos
Adenosina/metabolismo , Compostos Aza/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Oxazinas/metabolismo , Polifosfatos/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Adenosina/química , Compostos Aza/química , DNA Polimerase Dirigida por DNA/química , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Desoxiguanosina/metabolismo , Estrutura Molecular , Oxazinas/química , Polifosfatos/química
7.
Chem Commun (Camb) ; 55(77): 11511-11514, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31490471

RESUMO

A short metallofullere-peapod of Y2@C79N⊂[4]CHBC was constructed. The strong confinement effect from the large π-extended [4]CHBC nanoring induces molecular orientation of the wrapped Y2@C79N, which can be sensed by a Y2@C79N spin probe. The low susceptibility of the spin phase memory time (Tm) for the Y2@C79N spin was also found in a confined space.


Assuntos
Complexos de Coordenação/química , Fulerenos/química , Hidrocarbonetos Cíclicos/química , Marcadores de Spin , Ítrio/química , Compostos Aza/química , Teoria da Densidade Funcional , Conformação Molecular , Transição de Fase , Temperatura , Termodinâmica
8.
Arch Pharm (Weinheim) ; 352(11): e1900028, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31531897

RESUMO

Hemagglutinin is the surface protein of the influenza virus that mediates both binding and penetration of the virus into host cells. We here report on the synthesis and structure-activity relationship of some novel N-(1-thia-4-azaspiro[4.5]decan-4-yl)-carboxamide compounds carrying the 5-chloro-2-methoxybenzamide structure, designed as influenza virus fusion inhibitors. The carboxamides (1a-h, 2a-h) have a similar backbone structure as the fusion inhibitors that we reported on previously. Compounds 2b and 2d displayed inhibitory activity against influenza A/H3N2 virus replication (average antiviral EC50 : 2.1 µM for 2b and 3.4 µM for 2d). Data obtained in the hemolysis inhibition assay supported that these compounds act as inhibitors of the influenza virus hemagglutinin-mediated fusion process.


Assuntos
Antivirais/farmacologia , Compostos Aza/farmacologia , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Compostos de Espiro/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 182: 111669, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494473

RESUMO

A series of 2,8-diazaspiro[4.5]decan-1-one derivatives were designed, synthesized and screened for their inhibition activities against chitin synthase (CHS) and antimicrobial activities in vitro. The biological assays revealed that compounds 4a, 4e, 4h, 4j, 4o, 4q and 4r exhibited moderated to excellent potency against CHS with IC50 values ranging from 0.12 to 0.29 mM. Compounds 4e, 4j with IC50 value of 0.13 mM, 0.12 mM respectively, showed excellent inhibition potency among these compounds, which were similar to that of polyoxin B whose IC50 value was 0.08 mM. Meanwhile, the screening of the antifungal activity showed that compounds 4j and 4r had the same potency of inhibiting the growth of A. fumigatus with MIC value of 0.08 mmol/L. Compound 4d displayed excellent activity against C. albicans (ATCC 90023) with MIC value of 0.04 mmol/L, which was superior to fluconazole (0.104 mmol/L) and polyoxin B (0.129 mmol/L). The result of antibacterial assay showed that these compounds had little potency against those selected bacteria strains including three Gram-positive bacteria and three Gram-negative bacteria. Furthermore, the combination use of 4c-fluconazole, 4i-fluconazole, 4j-fluconazole, and 4o-fluconazole against C. albicans,A. fumigatus and A. flavus showed additive or synergistic effects. These results indicated that the designed compounds serve as potential chitin synthase inhibitors and have selectively antifungal activities.


Assuntos
Antifúngicos/farmacologia , Aspergillus flavus/efeitos dos fármacos , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Quitina Sintase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Quitina Sintase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
10.
Macromol Rapid Commun ; 40(21): e1900342, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31486180

RESUMO

The combination of efficient and harmonious aza-Michael and thiol-Michael reactions in one pot is first reported for the convenient synthesis of thermo-, oxidation-, pH-, and CO2 -responsive polymers. The simultaneous two-type Michael reactions are proved to proceed smoothly without additional catalyst. The dithiol and diamine are involved in the copolymerization competitively and thus in a random distribution. A wide range of commercially available starting materials are utilized for the simultaneous two-type Michael reactions in one pot to obtain various responsive polymers with different structures. The cloud point of the thermo-responsive polymers is easily tuned by adjusting the copolymerization ratio of monomers or using monomers with different structures. Besides, the oxidation- and pH-/CO2 - responsiveness are also demonstrated.


Assuntos
Compostos Aza/química , Dióxido de Carbono/química , Técnicas de Química Sintética , Polímeros/síntese química , Compostos de Sulfidrila/química , Temperatura , Concentração de Íons de Hidrogênio , Estrutura Molecular , Oxirredução , Polimerização , Polímeros/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
11.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374998

RESUMO

A series of 2-nm gold nanoparticles passivated with different thiols all featuring at least one triazacyclonanone-Zn(II) complex and different flanking units (a second Zn(II) complex, a triethyleneoxymethyl derivative or a guanidinium of arginine of a peptide) were prepared and studied for their efficiency in the cleavage of the RNA-model substrate 2-hydroxypropyl-p-nitrophenyl phosphate. The source of catalysis for each of them was elucidated from the kinetic analysis (Michaelis-Menten profiles, pH dependence and kinetic isotope effect). The data indicated that two different mechanisms were operative: One involving two Zn(II) complexes and the other one involving a single Zn(II) complex and a flanking guanidinium cation. The mechanism based on a dinuclear catalytic site appeared more efficient than the one based on the cooperativity between a metal complex and a guanidinium.


Assuntos
Compostos Aza/química , Complexos de Coordenação/química , Nanopartículas Metálicas/química , Piperidinas/química , RNA/química , Catálise , Ouro/química , Cinética , Modelos Moleculares , Estrutura Molecular , Compostos de Sulfidrila/química , Zinco/química
12.
Eur J Med Chem ; 180: 321-339, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31323617

RESUMO

Macrolides are widely prescribed in clinic to treat various respiratory tract infections. However, due to their inappropriate use, the prevalence of macrolide-resistant strains among clinical isolates has become a concern for public health. Therefore, novel macrolides skeleton structures against resistant pathogens are badly needed. Thus, three series of novel 15-membered 11a-azahomoclarithromycin derivatives (series A-C) with the 1, 2, 3-triazole side chain were designed and synthesized through creatively opening the ring of clarithromycin (CAM), expanding the ring properly and introducing a suitable side chain of 1, 2, 3-triazole at the C12 and C13 positions, and evaluated for their antibacterial activity. The antibacterial results indicated that compounds 38b, 38l and 38v possessed strong antibacterial activity against Staphylococcus aureus ATCC25923 (0.25 µg/mL) and Bacillus subtilis ATCC9372 (0.25 µg/mL). Furthermore, compounds 9e and 38g were found to exhibit promising potent activity (8 µg/mL) against Streptococcus pneumonia AB11 expressing the ermB and mefA genes. In addition, the determination of minimum bactericidal concentration (MBC) indicated that the most promising compounds 38b, 38l, 38v, 9e and 38g were excellent bacteriostatic agents. The bactericidal curve showed that 9e exhibited antibacterial activity through bacteriostatic mechanism. Finally, 38b, 38l and 38v were confirmed to be non-toxic to MCF-7 breast cancer cells up to a concentration of 32 µg/mL in preliminary cytotoxicity assay. In summary, 38b, 38l, 38v, 9e and 38g can be served as lead compounds to provide a new perspective for further structural optimization.


Assuntos
Antibacterianos/farmacologia , Compostos Aza/farmacologia , Claritromicina/farmacologia , Desenho de Fármacos , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Compostos Aza/síntese química , Compostos Aza/química , Bacillus subtilis/efeitos dos fármacos , Claritromicina/síntese química , Claritromicina/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/genética , Relação Estrutura-Atividade , Triazóis/química
13.
Future Med Chem ; 11(10): 1091-1106, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31280669

RESUMO

Aim: Anion/cation symport across cellular membranes may lead to cell apoptosis and be developed as a strategy for new anticancer drug discovery. Methodology: Four aza-crown ether-squaramide conjugates were synthesized and characterized. Their anion recognition, anion/cation symport, cytotoxicity and probable mechanism of action were investigated in details. Conclusion: These conjugates are able to form ion-pairing complexes with chloride anions and facilitate the transmembrane transport of anions via an anion/cation symport process. They can disrupt the cellular homeostasis of chloride anions and sodium cations and induce the basification of acidic organelles in live cells. These conjugates exhibit moderate cytotoxicity toward the tested cancer cells and trigger cell apoptosis by mediating the influx of chloride anions and sodium cations into live cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Transporte de Íons/efeitos dos fármacos , Quinina/análogos & derivados , Ânions/metabolismo , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Cátions/metabolismo , Linhagem Celular Tumoral , Éteres de Coroa/síntese química , Éteres de Coroa/química , Éteres de Coroa/farmacologia , Descoberta de Drogas , Humanos , Neoplasias/tratamento farmacológico , Quinina/síntese química , Quinina/química , Quinina/farmacologia
14.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1122-1123: 78-82, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163324

RESUMO

Selitrectinib is a next generation tropomyosin receptor kinase (TRK) inhibitor developed to overcome acquired resistance to first generation TRK inhibitors. The drug is a cyclic analogue of larotrectinib. An existing bioanalytical assay for larotrectinib was therefore redesigned for selitrectinib. The assay used liquid chromatography-electrospray tandem mass spectrometry in positive selected reaction monitoring mode. Mouse plasma and tissue homogenates of brain, heart, kidney, liver, lung, small intestine, spleen, and testis were pretreated using acetonitrile protein precipitation with larotrectinib added as internal standard. Successful validation using current guidelines was obtained in the range 0.5-1000 ng/ml. Precision was within 5-12% and accuracy within 91-108% for all matrices investigated. The drug was stable in all matrices under the relevant storage conditions. Pharmacokinetics and tissue distribution of selitrectinib were monitored in a pilot study in mice demonstrating the applicability of the presented assay.


Assuntos
Compostos Aza/análise , Compostos Aza/farmacocinética , Cromatografia Líquida/métodos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Compostos Aza/química , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Inibidores de Proteínas Quinases/química , Reprodutibilidade dos Testes , Distribuição Tecidual
15.
Molecules ; 24(10)2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109055

RESUMO

Cα to N substitution in aza-amino acids imposes local conformational constraints, changes in hydrogen bonding properties, and leads to adaptive chirality at the nitrogen atom. These properties can be exploited in mimicry and stabilization of peptide secondary structures and self-assembly. Here, the effect of a single aza-amino acid incorporation located in the upper ß-strand at a hydrogen-bonded (HB) site of a ß-hairpin model peptide (H-Arg-Tyr-Val-Glu-Val-d-Pro-Gly-Orn-Lys-Ile-Leu-Gln-NH2) is reported. Specifically, analogs in which valine3 was substituted for aza-valine3 or aza-glycine3 were synthesized, and their ß-hairpin stabilities were examined using Nuclear Magnetic Resonance (NMR) spectroscopy. The azapeptide analogs were found to destabilize ß-hairpin formation compared to the parent peptide. The aza-valine3 residue was more disruptive of ß-hairpin geometry than its aza-glycine3 counterpart.


Assuntos
Aminoácidos/química , Compostos Aza/química , Compostos Aza/farmacologia , Estrutura Secundária de Proteína/efeitos dos fármacos , Proteínas/química , Sequência de Aminoácidos , Ligação de Hidrogênio , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Dobramento de Proteína , Técnicas de Síntese em Fase Sólida
16.
Electrophoresis ; 40(14): 1824-1829, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31106865

RESUMO

A variety of evidences are found at crime scenes. Fingerprint and DNA evidences are especially important in the process of identifying personal sources. Among evidences found at crime scenes, cigarette butts are important because they might contain both fingerprints and DNA. In this study, latent fingerprints were detected in cigarette butts using 1,8-diazafluoren-9-one (DFO) and 1,2-Indanedione/zinc chloride (1,2-IND/Zn). Next, DNA extraction and real-time qPCR were performed to quantify and identify the DNA present. Short tandem repeat (STR) profiling was also performed. The results showed that the quantity of DNA recovered was decreased by 16% in DFO-treated cigarettes and by 27% in 1,2-IND/Zn-treated cigarettes when compared to untreated controls. When the STR profiling results were compared with those of the control sample, DFO, and 1,2-IND/Zn reagent-treated DNA samples showed individualized genotyping at several loci. Results of this study showed that when cigarette butts were found, DFO and 1,2-IND/Zn reagents could be used for DNA profiling after fingerprint identification. However, the effect of DFO on STR profiling was less than that of 1,2-IND/Zn. Therefore, we recommend the use of DFO for fingerprinting cigarette butts if further DNA processing is planned.


Assuntos
Compostos Aza/química , Impressões Digitais de DNA/métodos , DNA/análise , Saliva/química , Cloretos/química , Eletroforese Capilar , Corantes Fluorescentes , Medicina Legal/métodos , Humanos , Indanos/química , Reação em Cadeia da Polimerase em Tempo Real , Espectrometria de Fluorescência , Compostos de Zinco/química
17.
ACS Chem Biol ; 14(6): 1110-1114, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31091068

RESUMO

Tyrosyl DNA phosphodiesterase 2 (TDP2) facilitates the repair of topoisomerase II (TOP2)-linked DNA double-strand breaks and, as a consequence, is required for cellular resistance to TOP2 "poisons". Recently, a deazaflavin series of compounds were identified as potent inhibitors of TDP2, in vitro. Here, however, we show that while some deazaflavins can induce cellular sensitivity to the TOP2 poison etoposide, they do so independently of TDP2 status. Consistent with this, both the cellular level of etoposide-induced TOP2 cleavage complexes and the intracellular concentration of etoposide was increased by incubation with deazaflavin, suggesting an impact of these compounds on etoposide uptake/efflux. In addition, deazaflavin failed to increase the level of TOP2 cleavage complexes or sensitivity induced by m-AMSA, which is a different class of TOP2 poison to which TDP2-defective cells are also sensitive. In conclusion, while deazaflavins are potent inhibitors of TDP2 in vitro, their limited cell permeability and likely interference with etoposide influx/efflux limits their utility in cells.


Assuntos
Compostos Aza/química , Proteínas de Ligação a DNA/antagonistas & inibidores , Etoposídeo/farmacocinética , Flavinas/farmacologia , Inibidores da Topoisomerase II/farmacocinética , Animais , Transporte Biológico , Linhagem Celular , Galinhas , Flavinas/química , Flavinas/farmacocinética , Humanos , Diester Fosfórico Hidrolases , Bibliotecas de Moléculas Pequenas/farmacologia
18.
Arch Pharm (Weinheim) ; 352(6): e1800330, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31073993

RESUMO

A series of 1-thia-4-azaspiro[4.5]decan-3-ones bearing an amide group at C-4 and various substitutions at C-2 and C-8 were synthesized and evaluated against human coronavirus and influenza virus. Compounds 7m, 7n, 8k, 8l, 8m, 8n, and 8p were found to inhibit human coronavirus 229E replication. The most active compound was N-(2-methyl-8-tert-butyl-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)-3-phenylpropanamide (8n), with an EC50 value of 5.5 µM, comparable to the known coronavirus inhibitor, (Z)-N-[3-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]-3-oxo-1-phenylprop-1-en-2-yl]benzamide (K22). Compound 8n and structural analogs were devoid of anti-influenza virus activity, although their scaffold is shared with a previously discovered class of H3 hemagglutinin-specific influenza virus fusion inhibitors. These findings point to the 1-thia-4-azaspiro[4.5]decan-3-one scaffold as a versatile chemical structure with high relevance for antiviral drug development.


Assuntos
Antivirais/síntese química , Compostos Aza/síntese química , Coronavirus/efeitos dos fármacos , Desenho de Fármacos , Compostos de Espiro/síntese química , Animais , Antivirais/química , Antivirais/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Efeito Citopatogênico Viral/efeitos dos fármacos , Cães , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Humanos , Células Madin Darby de Rim Canino , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
19.
Dalton Trans ; 48(20): 6767-6776, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31017131

RESUMO

The coordination chemistry of the first row transition metal trifluorides with terpy (2,2':6',2''-terpyridine) and Me3-tacn (1,4,7-trimethyl-1,4,7-triazacyclononane) was explored to identify potential systems for 18F radiolabelling. The complexes [MF3(L)] (M = Cr, Mn, Fe, Co; L = Me3-tacn, terpy) were synthesised and fully characterised by UV-vis and IR spectroscopy, microanalysis, and, for the diamagnetic [CoF3(L)], using 1H, 19F{1H} and 59Co NMR spectroscopy. Single crystal X-ray analyses are reported for [MF3(Me3-tacn)] (M = Mn, Co), [FeF3(terpy)] and [FeF3(BnMe2-tacn)]. Stability tests on [MF3(Me3-tacn)] (M = Cr, Mn, Fe) and [M'F3(terpy)] (M' = Cr, Fe) were performed and Cl/19F halide exchange reactions on [CrCl3(Me3-tacn)] using [Me4N]F in anhydrous MeCN solution, and [FeCl3(Me3-tacn)] using [Me4N]F in anhydrous MeCN or KF in aqueous MeCN solution were also carried out. Halide exchange reactions proved to be successful in forming [FeF3(Me3-tacn)] in aqueous MeCN solution within 30 minutes. Based upon the clean Cl/F exchange and the good stability observed for [FeF3(Me3-tacn)] in a range of competitive media, this was identified as a possible candidate for radiolabelling. 18F/19F isotopic exchange was achieved by addition of [18F]F- in the cyclotron target water to a MeCN solution of the benzyl-substituted analogue, [FeF3(BnMe2-tacn)], at a range of concentrations down to 24 nM with heating to 80 °C for 10 min.; the resulting [Fe18F19F2(BnMe2-tacn)] shows radiochemical purity (RCP) ≥90% after 2 h in a range of formulations, including 10% EtOH/phosphate buffered saline (PBS) and 10% EtOH/human serum albumin (HSA). This is the first reported complex with a transition metal directly bonded to [18F]F-.


Assuntos
Quelantes/química , Complexos de Coordenação/química , Fluoretos/química , Elementos de Transição/química , Compostos Aza/química , Complexos de Coordenação/síntese química , Flúor , Radioisótopos de Flúor , Ligantes , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Piridinas/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
20.
Bioorg Med Chem ; 27(10): 1990-1996, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30975500

RESUMO

Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (5) (Ki = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5. The radioiodine labeled probe [125I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([125I]10) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both in vitro and in vivo. Co-injection of [125I]10 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo, indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.


Assuntos
Compostos Aza/química , Piperidinas/química , Compostos Radiofarmacêuticos/síntese química , Receptores sigma/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Radioisótopos do Iodo/química , Marcação por Isótopo , Masculino , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Receptores sigma/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Transplante Heterólogo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA