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1.
IUCrdata ; 9(Pt 5): x240431, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38846558

RESUMO

In the structure of the title complex, [Zn(C4H2FN2O2)(C10H24N4)]ClO4, the zinc(II) ion forms coordination bonds with the four nitro-gen atoms of cyclam (1,4,8,11-tetra-aza-cyclo-tetra-decane or [14]aneN4) as well as with the nitro-gen atom of a deprotonated 5-fluoro-uracil ion (FU-). Cyclam adopts a trans-I type conformation within this structure. The coordination structure of the zinc(II) ion is a square pyramid with a distorted base plane formed by the four nitro-gen atoms of the cyclam. FU- engages in inter-molecular hydrogen bonding with neighboring FU- mol-ecules and with the cyclam mol-ecule.

2.
IUCrdata ; 8(Pt 6): x230462, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37936873

RESUMO

In the title dinuclear CuII complex, [Cu2(NO3)(C24H46N8)(H2O)](NO3)3·3H2O, the two CuII mol-ecules both have a square-pyramidal geometry, but the ligands in the axial positions are different: a water mol-ecule and a nitrate ion. All nitrate ions, water mol-ecules, and N-H groups are involved in an inter-molecular hydrogen-bond network.

3.
Chem Pharm Bull (Tokyo) ; 71(7): 545-551, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37394603

RESUMO

We designed and synthesized a chiral ligand N-(anthracen-9-ylmethyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)ethanamine (APPE) DNA photocleavage agent to investigate the effects of chirality of bis(2-picolyl)amine on the DNA photocleavage activity of metal complexes. The structures of ZnII and CoII complexes in APPE were analyzed via X-ray crystallography and fluorometric titration. APPE formed metal complexes with a 1 : 1 stoichiometry in both the crystalline and solution states. Fluorometric titration was used to show that the ZnII and CoII association constants of these complexes (log Kas) were 4.95 and 5.39, respectively. The synthesized complexes were found to cleave pUC19 plasmid DNA when irradiated at 370 nm. The DNA photocleavage activity of the ZnII complex was higher than that of the CoII complex. The absolute configuration of the methyl-attached carbon did not affect DNA cleavage activity and, unfortunately, an achiral APPE derivative without the methyl group (ABPM) was found to perform DNA photocleavage more effectively than APPE. One reason for this may be that the methyl group suppressed the structural flexibility of the photosensitizer. These results will be useful for the design of new photoreactive reagents.


Assuntos
Complexos de Coordenação , Zinco , Zinco/química , Cobalto/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Cobre/química , Aminas/química , DNA/química , Cristalografia por Raios X , Ligantes
4.
Bioorg Med Chem Lett ; 88: 129287, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37094725

RESUMO

We report the synthesis of a peptide nucleic acid (PNA) monomer containing N4-bis(aminomethyl)benzoylated cytosine (BzC2+ base). The BzC2+ monomer was incorporated into PNA oligomers using Fmoc-based solid-phase synthesis. The BzC2+ base in PNA had two positive charges and exhibited greater affinity for DNA G base than the natural C base. The BzC2+ base stabilized PNA-DNA heteroduplexes through electrostatic attractions, even in high salt conditions. The two positive charges on the BzC2+ residue did not compromise the sequence specificity of PNA oligomers. These insights will aid the future design of cationic nucleobases.


Assuntos
Ácidos Nucleicos Peptídicos , Ácidos Nucleicos Peptídicos/química , Citosina , DNA/química
5.
IUCrdata ; 7(Pt 8): x220854, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36340980

RESUMO

The two ZnII atoms in the crystal structure of the title complex, [Zn(NO3)2(C10H24N4)]·CH3OH, have a distorted octa-hedral coordination sphere, defined by 1,4,8,11-tetra-aza-cyclo-tetra-decane (cyclam) N atoms in the equatorial plane and nitrate O atoms in the axial sites. The conformation of the cyclam is trans-III (R, R, S, S), which is typical for metal-cyclam complexes. Nitrate anions are involved in intra- and inter-molecular hydrogen bonding with the N-H groups of the ZnII-cyclam unit. Together with the methanol solvent mol-ecule, the hydrogen-bonding network connects the ZnII-cyclam units into ribbons running parallel to the a axis.

6.
Bioorg Med Chem Lett ; 39: 127850, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33662538

RESUMO

We report the synthesis of a peptide nucleic acid (PNA) monomer containing preQ1, a positively charged guanine analogue. The new monomer was incorporated into PNA oligomers using standard Fmoc-chemistry-based solid-phase synthesis. The preQ1 unit-containing PNA oligomers exhibited improved affinity for their complementary DNA through electrostatic attraction, and their sequence specificity was not compromised. It could be beneficial to incorporate preQ1 into PNA oligomers instead of guanine when creating antisense/antigene agents or research tools.


Assuntos
Ácidos Nucleicos Peptídicos/síntese química , Pirimidinonas/química , Pirróis/química , Estrutura Molecular , Ácidos Nucleicos Peptídicos/química
7.
Chem Pharm Bull (Tokyo) ; 68(8): 773-778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741919

RESUMO

Lower urinary tract symptoms (LUTS) induced by anticholinergic drug action impair the QOL of patients and are associated with a poor prognosis. Therefore, it is expedient to develop methods of predicting the anticholinergic side effects of drugs, which we aimed to achieve in this study using a quantitative structure-activity relationship (QSAR) and docking study with molecular operations environment (MOE; Molecular Simulation Informatics Systems [MOLSIS], Inc.) In the QSAR simulation, the QSAR model built using the partial least squares regression (PLS) and genetic algorithm-multiple linear regression (GA-MLR) methods showed remarkable coefficient of determination (R2) and XR2 values. In the docking study, a specific relationship was identified between the adjusted docking score (-S) and bioactivity (pKi) values. In conclusion, the methods developed could be useful for in silico risk assessment of LUTS, and plans are potentially applicable to numerous drugs with anticholinergic activity that induce serious side effects, limiting their use.


Assuntos
Antagonistas Colinérgicos/química , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Algoritmos , Sítios de Ligação , Antagonistas Colinérgicos/uso terapêutico , Humanos , Análise dos Mínimos Quadrados , Modelos Lineares , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/patologia , Receptor Muscarínico M3/química , Receptor Muscarínico M3/metabolismo
8.
Pharmaceuticals (Basel) ; 13(3)2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32106507

RESUMO

Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the aryl hydrocarbon receptor (AhR) E3 ligase complex and induce the AhR-dependent degradation of target proteins. However, these chimeras contain a hydrophobic AhR E3 ligand, and thus, degrade target proteins even in cells that do not express AhR. In this study, we synthesized new compounds in which the AhR ligands were replaced with a hydrophobic adamantane moiety to investigate the mechanisms of AhR-independent degradation. Our results showed that the compounds, 2, 3, and 16 induced significant degradation of some target proteins in cells that do not express AhR, similar to the chimeras containing AhR ligands. However, in cells expressing AhR, 2, 3, and 16 did not induce the degradation of other target proteins, in contrast with their response to chimeras containing AhR ligands. Overall, it was suggested that target proteins susceptible to the hydrophobic tagging system are degraded by chimeras containing hydrophobic AhR ligands even without AhR.

9.
ACS Chem Biol ; 14(12): 2822-2832, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31580635

RESUMO

Targeted protein degradation using chimeric small molecules such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) is an emerging modality in drug discovery. Here, we expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating ß-naphthoflavone (ß-NF) as a ligand, we developed a novel class of chimeric molecules that recruit the arylhydrocarbon receptor (AhR) E3 ligase complex. ß-NF-ATRA, a chimeric degrader directed against cellular retinoic acid binding proteins (CRABPs), induced the AhR-dependent degradation of CRABP-1 and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound ITE-ATRA, in which an alternative AhR ligand was used, also degraded CRABP proteins. Finally, we developed a chimeric compound ß-NF-JQ1 that is directed against bromodomain-containing (BRD) proteins using ß-NF as an AhR ligand. ß-NF-JQ1 induced the interaction of AhR and BRD proteins and displayed effective anticancer activity that correlated with protein knockdown activity. These results demonstrate a novel class of chimeric degrader molecules based on the ability to bring a target protein and an AhR E3 ligase into close proximity.


Assuntos
Receptores de Hidrocarboneto Arílico/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Feminino , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Ligantes , Células MCF-7 , Receptores do Ácido Retinoico/metabolismo , Bibliotecas de Moléculas Pequenas/química
10.
Biol Pharm Bull ; 42(6): 982-988, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155595

RESUMO

Staphylococcus aureus produces a variety of exoproteins that interfere with host immune systems. We attempted to purify cytotoxins against human leukocytic cells from the culture supernatant of S. aureus by a combination of ammonium sulfate precipitation, ion-exchange chromatography on a CM-cellulose column and HPLC on a Mono S 5/50 column. A major protein possessing cytotoxicity to HL60 human promyelocytic leukemia cells was purified, and the protein was identified as α-hemolysin (Hla, α-toxin) based on its molecular weight (34 kDa) and N-terminal amino acid sequence. Flow cytometric analysis suggested differential cytotoxicity of Hla against different human peripheral blood leukocyte populations. After cell fractionation with density-gradient centrifugation, we found that peripheral blood mononuclear cells (PBMCs) were more susceptible to Hla than polymorphonuclear leukocytes. Moreover, cell surface marker analysis suggested that Hla exhibited slightly higher cytotoxicity against CD14-positive PBMCs (mainly monocytes) than CD3- or CD19-positive cells (T or B lymphocytes). From these results, we conclude that human leukocytes have different susceptibility to Hla depending on their cell lineages, and thereby the toxin may modulate the host immune response.


Assuntos
Toxinas Bacterianas/farmacologia , Proteínas Hemolisinas/farmacologia , Leucócitos/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucócitos/imunologia
11.
Bioorg Med Chem ; 26(23-24): 6146-6152, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30446437

RESUMO

Non-secosteroidal VDR ligands without any assymmetric carbon were designed and synthesized based on the structure of the previously reported non-secosteroidal VDR agonist LG190178. The VDR-agonistic activity of all synthesized compounds was evaluated, and 7b emerged as a potent agonist activity with an EC50 value of 9.26 nM. Moreover, a docking simulation analysis was also performed to determine the binding mode of 7b with VDR-LBD.


Assuntos
Compostos de Bifenilo/farmacologia , Receptores de Calcitriol/agonistas , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
12.
Bioorg Med Chem ; 26(20): 5494-5498, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30293794

RESUMO

Fluorescence labeling of the target molecules using a small molecule-based probe is superior than a method using genetically expressed green fluorescence protein (GFP) in terms of convenience in its preparation and functionalization. Fluorophore-nitrilotriacetic acid (NTA) conjugates with several ester protecting groups were synthesized and evaluated for their cell membrane permeability by fluorescence microscopy analysis. One of the derivatives, acetoxymethyl (AM)-protected NTA conjugate is hydrolyzed, resulting in intracellular accumulation, thus providing localized fluorescence intensity in cells. This modification is expected as an effective method for converting a non-cell membrane permeable NTA-BODIPY conjugates to a cell membrane permeable derivatives.


Assuntos
Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/metabolismo , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/metabolismo , Linhagem Celular , Permeabilidade da Membrana Celular , Fluorescência , Corantes Fluorescentes/síntese química , Humanos , Hidrólise , Microscopia de Fluorescência , Ácido Nitrilotriacético/síntese química
13.
Bioorg Med Chem ; 26(8): 1638-1642, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29525335

RESUMO

The estrogen receptor (ER), a member of the nuclear receptor (NR) family, is involved in the regulation of physiological effects such as reproduction and bone homeostasis. Approximately 70% of human breast cancers are hormone-dependent and ERα-positive, and, thus, ER antagonists are broadly used in breast cancer therapy. We herein designed and synthesized a set of ER antagonists with a 4-heterocycle-4-phenylheptane skeleton.


Assuntos
Antagonistas do Receptor de Estrogênio/farmacologia , Heptanos/farmacologia , Indóis/farmacologia , Pirróis/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Antagonistas do Receptor de Estrogênio/síntese química , Antagonistas do Receptor de Estrogênio/química , Heptanos/síntese química , Heptanos/química , Humanos , Indóis/síntese química , Indóis/química , Ligantes , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Células Tumorais Cultivadas
14.
J Med Chem ; 61(2): 576-582, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28460164

RESUMO

In recent years, the induction of target-protein degradation via the ubiquitin-proteasome system (UPS) mediated by small molecules has attracted attention, and this approach has applications in pharmaceutical development. However, this technique requires a ligand for the target protein that can be incorporated into tailor-made molecules, and there are many proteins for which such ligands have not been found. In this study, we developed a protein-knockdown method that recognizes a His-tag fused to a protein of interest. This strategy theoretically allows comprehensive targeting of proteins of interest by a particular molecule recognizing the tag. As expected, our hybrid molecule 10 [SNIPER(CH6)] efficiently degraded His-tagged CRABP-II and Smad2 in cells. This system provides an easy method to determine the susceptibility of proteins of interest to UPS-mediated degradation. Furthermore, we hope that this method will become an efficient tool to analyze the function of the UPS.


Assuntos
Proteólise/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo , Biotina/química , Linhagem Celular , Cisteína/metabolismo , Histidina/química , Histidina/genética , Humanos , Leupeptinas/farmacologia , Maleimidas/química , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/química , Compostos Organometálicos/química , Inibidores de Proteassoma/farmacologia , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
15.
Chemistry ; 23(72): 18120-18124, 2017 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-29134704

RESUMO

The relationship between chiral centers and the helical-screw control of their peptides has already been reported, but it has yet to be elucidated in detail. A chiral four-membered ring α,α-disubstituted α-amino acid with a (R,R)-butane-2,3-diol acetal moiety at the γ-position, but no α-chiral carbon, was synthesized. X-ray crystallographic analysis unambiguously revealed that its homo-chiral heptapeptide formed right-handed (P) and left-handed (M) 310 -helical structures at a ratio of 1:1. They appeared to be enantiomeric at the peptide backbone, but diastereomeric with fourteen (R)-configuration chiral centers. Conformational analyses of homopeptides in solution also indicated that diastereomeric (P) and (M) helices existed at approximately equal amounts, with a slight preference toward right-handedness, and they quickly interchanged at room temperature. The circumstances of chiral centers are important for the control of their helical-screw direction.

16.
Bioorg Med Chem Lett ; 27(22): 4985-4988, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29050782

RESUMO

We previously developed a protein knockdown system by small-molecule hybrid compounds named SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers). Here we report a peptide-based protein knockdown system for inducing degradation of a transcriptional factor NOTCH1. The molecules designed were composed of two biologically active scaffolds: a peptide that binds to the surface of the target protein NOTCH1 and a small-molecule MV1 that binds to the E3 ubiquitin ligase inhibitor of apoptosis protein (IAP), which are expected to cross-link these proteins in cells. Hybrid molecules specifically induced the degradation of the NOTCH1 protein by the proteasome. This system could be a useful method to develop various degradation inducers against a large number of proteins to which small-molecule ligands have not been found.


Assuntos
Peptídeos/metabolismo , Proteólise , Receptor Notch1/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Peptídeos/química , Estrutura Terciária de Proteína , Receptor Notch1/química , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo
17.
Bioorg Med Chem Lett ; 27(17): 3950-3953, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28789896

RESUMO

Lysine-based amphipathic nonapeptides, including homochiral peptides [Ac-(l-Lys-l-Lys-Xaa)3-NH2 (Xaa=Gly, Ala, Aib, Ac5c, or Ac6c) and Ac-(d-Lys-d-Lys-Aib)3-NH2], a heterochiral peptide [Ac-(l-Lys-d-Lys-Aib)3-NH2], and a racemic mixture of diastereomeric peptides [Ac-(rac-Lys-rac-Lys-Aib)3-NH2] were designed and synthesized to investigate the relationship between their preferred secondary structures and their antimicrobial activity. Peptide 5, [Ac-(l-Lys-l-Lys-Ac6c)3-NH2] formed a stable α-helical structure and exhibited strong activity against Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa).


Assuntos
Aminoácidos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Escherichia coli/efeitos dos fármacos , Lisina/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Aminoácidos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Relação Dose-Resposta a Droga , Lisina/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 27(18): 4478-4481, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28807436

RESUMO

We designed and synthesized hybrid molecules for a protein knockdown method based on the recognition of a His-tag fused to a protein of interest (POI). The synthesized target protein degradation inducers contained three functional moieties: a His-tag ligand (nickel nitrilotriacetic acid [Ni-NTA]), an E3 ligand (bestatin [BS] or MV1), and a carrier peptide (Tat or nonaarginine [R9]). The designed hybrid molecules, BS-Tat-Ni-NTA, MV1-Tat-Ni-NTA, BS-R9-Ni-NTA, and MV1-R9-Ni-NTA, efficiently degraded His-tagged cellular retinoic acid binding protein 2 via the ubiquitin-proteasome system (UPS). This system will become a useful tool for research into selective protein degradation inducers that act via the UPS.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Leucina/análogos & derivados , Ácido Nitrilotriacético/análogos & derivados , Oligopeptídeos/farmacologia , Compostos Organometálicos/farmacologia , Receptores do Ácido Retinoico/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Linhagem Celular , Peptídeos Penetradores de Células/química , Relação Dose-Resposta a Droga , Histidina/metabolismo , Humanos , Leucina/química , Leucina/farmacologia , Ligantes , Estrutura Molecular , Ácido Nitrilotriacético/química , Ácido Nitrilotriacético/farmacologia , Oligopeptídeos/química , Compostos Organometálicos/química , Receptores do Ácido Retinoico/metabolismo , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/metabolismo
19.
Org Biomol Chem ; 15(30): 6302-6305, 2017 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-28678242

RESUMO

We developed a novel methodology using cyclic α,α-disubstituted α-amino acids (dAAs) with an acetal-side chain to control peptide secondary structures. The introduction of cyclic dAAs into peptides contributed to the stabilization of peptide secondary structures as a helix, while an acidic treatment of peptides resulted in a marked conformational change.


Assuntos
Oligopeptídeos/química , Acetais/química , Concentração de Íons de Hidrogênio , Estrutura Secundária de Proteína
20.
Bioorg Med Chem Lett ; 27(15): 3337-3341, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28610975

RESUMO

Here we report the synthesis of new PNA monomers for pseudocomplementary PNA (pcPNA) that are fully compatible with standard Fmoc chemistry. The thiocarbonyl group of the 2-thiouracil (sU) monomer was protected with the 4-methoxy-2-methybenzyl group (MMPM), while the exocyclic amino groups of diaminopurine (D) were protected with Boc groups. The newly synthesized monomers were incorporated into a 10-mer PNA oligomer using standard Fmoc chemistry for solid-phase synthesis. Oligomerization proceeded smoothly and the HPLC and MALDI-TOF MS analyses indicated that there was no remaining MMPM on the sU nucleobase. The new PNA monomers reported here would facilitate a wide range of applications, such as antigene PNAs and DNA nanotechnologies.


Assuntos
Ácidos Nucleicos Peptídicos/síntese química , Técnicas de Síntese em Fase Sólida , Estrutura Molecular , Ácidos Nucleicos Peptídicos/química
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