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1.
Anal Chem ; 91(14): 9119-9128, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31260264

RESUMEN

Screening and identifying unknown erectile dysfunction (ED) drugs and analogues, which are often illicitly added to health supplements, is a challenging analytical task. The analytical technique most commonly used for this purpose, liquid chromatography-tandem mass spectrometry (LC-MS/MS), is based on the strategy of searching the LC-MS/MS spectra of target compounds against database spectra. However, such a strategy cannot be applied to unknown ED drugs and analogues. To overcome this dilemma, we have constructed a standalone software named AI-SIDA (artificial intelligence screener of illicit drugs and analogues). AI-SIDA consists of three layers: LC-MS/MS viewer, AI classifier, and Identifier. In the second AI classifier layer, an artificial neural network (ANN) classification model, which was constructed by training 149 LC-MS/MS spectra (including 27 sildenafil-type, 6 vardenafil-type, 11 tadalafil-type ED drugs/analogues and other 105 compounds), is included to classify the LC-MS/MS spectra of the query compound into four categories: i.e., sildenafil, vardenafil, and tadalafil families and non-ED compounds. This ANN model was found to show 100% classification accuracy for the 187 LC-MS/MS modeling and test data sets. In the third Identifier layer, three search algorithms (pick-count scoring, simple similarity search, and hybrid similarity search) are implemented. In particular, the hybrid similarity search was found to be very powerful in identifying unknown ED drugs/analogues with a single modification from the library ED drugs/analogues. Altogether, the AI-SIDA software provides a very useful and powerful platform for screening unknown ED drugs and analogues.


Asunto(s)
Cromatografía Liquida/estadística & datos numéricos , Disfunción Eréctil/tratamiento farmacológico , Programas Informáticos , Espectrometría de Masas en Tándem/estadística & datos numéricos , Agentes Urológicos/análisis , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Estructura Molecular , Redes Neurales de la Computación , Prueba de Estudio Conceptual , Agentes Urológicos/química
2.
Langmuir ; 33(10): 2590-2595, 2017 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-28005379

RESUMEN

The bioinspired design of ligands for nanoparticle coating with remarkable precision in controlling anisotropic connectivity and with universal binding efficiency to the membrane has made a great impact on nanoparticle self-assembly. We utilize the HIV-1-derived trans-activator of transcription peptide (TAT), a member of the cell-penetrating peptides, as a soft shell coating on gold nanoparticles (GNPs) and characterize TAT pepide-mediated binding behaviors of GNPs on the lipid membrane. Whereas the peptides enable GNPs to firmly attach to the membrane, the binding structures are driven by two electrostatic forces: the interparticle peptide repulsion and the peptide-membrane attraction. Although transmission electron microscopy images showed that the densities of membrane-embedded GNPs were almost equal, X-ray reflectivity revealed a significant difference in binding structures of GNPs along the surface normal upon the increase of charge densities (ϕ) of the membrane. In particular, GNPs were densely suspended at ϕ = 70% while they adopted an additional well-defined layer underneath the membrane at ϕ = 100%, in addition to a translocation of the initially bound particles into the membrane. The observed behaviors of GNPs manifest a 3D to 2D transformation of the self-assembled structures from the diffused state to the closely packed state with the increase in the charge density of the membrane. The present study also provides insights on the binding mechanisms of the cell-penetrating peptide-coated nanoparticles to the lipid membranes, which is a common theme of delivery systems in pharmaceutical research.


Asunto(s)
Nanopartículas del Metal , Fenómenos Biofísicos , Oro , Infecciones por VIH , Lípidos
3.
Mass Spectrom Rev ; 34(2): 116-32, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-24863492

RESUMEN

In recent years, a number of novel tandem mass spectrometry approaches utilizing radical-driven peptide gas-phase fragmentation chemistry have been developed. These approaches show a peptide fragmentation pattern quite different from that of collision-induced dissociation (CID). The peptide fragmentation features of these approaches share some in common with electron capture dissociation (ECD) or electron transfer dissociation (ETD) without the use of sophisticated equipment such as a Fourier-transform mass spectrometer. For example, Siu and coworkers showed that CID of transition metal (ligand)-peptide ternary complexes led to the formation of peptide radical ions through dissociative electron transfer (Chu et al., 2000. J Phys Chem B 104:3393-3397). The subsequent collisional activation of the generated radical ions resulted in a number of characteristic product ions, including a, c, x, z-type fragments and notable side-chain losses. Another example is the free radical initiated peptide sequencing (FRIPS) approach, in which Porter et al. and Beauchamp et al. independently introduced a free radical initiator to the primary amine group of the lysine side chain or N-terminus of peptides (Masterson et al., 2004. J Am Chem Soc 126:720-721; Hodyss et al., 2005 J Am Chem Soc 127: 12436-12437). Photodetachment of gaseous multiply charged peptide anions (Joly et al., 2008. J Am Chem Soc 130:13832-13833) and UV photodissociation of photolabile radical precursors including a C-I bond (Ly & Julian, 2008. J Am Chem Soc 130:351-358; Ly & Julian, 2009. J Am Soc Mass Spectrom 20:1148-1158) also provide another route to generate radical ions. In this review, we provide a brief summary of recent results obtained through the radical-driven peptide backbone dissociation tandem mass spectrometry approach.


Asunto(s)
Aminoácidos/química , Radicales Libres/química , Gases/análisis , Iones/química , Fragmentos de Péptidos/análisis , Espectrometría de Masas en Tándem/métodos , Gases/química , Humanos , Cinética , Fragmentos de Péptidos/química , Procesos Fotoquímicos , Electricidad Estática , Espectrometría de Masas en Tándem/instrumentación , Temperatura , Termodinámica , Rayos Ultravioleta
4.
Phys Chem Chem Phys ; 16(20): 9591-601, 2014 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-24728507

RESUMEN

Imidazolium-based ionic liquids having different anions 1-butyl-3-methylimidazolium ([BMIM]X: X = Cl(-), Br(-), I(-), and BF4(-)) and their aqueous mixtures were investigated by IR absorption and proton NMR spectroscopy. The IR spectra of these ionic liquids in the CHx stretching region differed substantially, especially for C-H bonds in the imidazolium ring, and the NMR chemical shifts of protons in the imidazolium ring also varied markedly for ILs having different anions. Upon the introduction of water to screen the electrostatic forces and separate the ions, both IR and NMR spectra of [BMIM]X (X = Cl(-), Br(-), I(-)) showed significant changes, while those of [BMIM]BF4 did not change appreciably. H-D isotopic exchange rates of C(2)-H in [BMIM]X-D2O mixtures exhibited an order: C(2)-HCl > C(2)-HBr > C(2)-HI, while the C(2)-H of [BMIM]BF4 was not deuterated at all. These experimental findings, supported by DFT calculations, lead to the microscopic bulk configurations in which the anions and the protons of the cations in the halide ionic liquids have specific, hydrogen-bond type of interaction, while the BF4(-) anion does not participate in the specific interaction, but interacts less specifically by positioning itself more above the ring plane of the imidazolium cation. This structural change dictated by the anion type will work as a key element to build the structure-property relationship of ionic liquids.

5.
Chemosphere ; 363: 142840, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39019193

RESUMEN

Plasticizers are chemicals that make plastics flexible, and phthalates are commonly used. Due to the toxic effects of phthalates, there is increasing use of non-phthalate plasticizers like acetyl tributyl citrate (ATBC). ATBC has emerged as a safer alternative, yet concerns about its long-term safety persist due to its high leachability and potential endocrine-disrupting effects. This study aims to identify ATBC metabolites using human liver microsomes and suspect screening methods, and to explore potential urinary biomarkers for ATBC exposure. Using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry, we identified ATBC metabolites, including acetyl dibutyl citrate (ADBC), tributyl citrate (TBC), and dibutyl citrate (DBC). Urine samples from 15 participants revealed the presence of ADBC in 5, TBC in 11, and DBC in all samples, with DBC concentrations pointedly higher than the other metabolites. These metabolites show promise as biomarkers for ATBC exposure, though further validation with human data is required. Our results underscore the need for comprehensive studies on ATBC metabolism, exposure pathways, and urinary excretion to accurately assess human exposure levels.


Asunto(s)
Citratos , Microsomas Hepáticos , Plastificantes , Humanos , Microsomas Hepáticos/metabolismo , Plastificantes/metabolismo , Citratos/orina , Citratos/metabolismo , Biomarcadores/orina , Biomarcadores/metabolismo , Cromatografía Líquida de Alta Presión , Adulto , Disruptores Endocrinos/orina , Disruptores Endocrinos/metabolismo
6.
Anal Chem ; 85(15): 7044-51, 2013 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-23802150

RESUMEN

Peptide dissociation behavior in TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)-based FRIPS (free radical initiated peptide sequencing) mass spectrometry was analyzed in both positive- and negative-ion modes for a number of peptides including angiotensin II, kinetensin, glycoprotein IIb fragment (296-306), des-Pro(2)-bradykinin, and ubiquitin tryptic fragment (43-48). In the positive mode, the ·Bz-C(O)-peptide radical species was produced exclusively at the initial collisional activation of o-TEMPO-Bz-C(O)-peptides, and two consecutive applications of collisional activation were needed to observe peptide backbone fragments. In contrast, in the negative-ion mode, a single application of collisional activation to o-TEMPO-Bz-C(O)-peptides produced extensive peptide backbone fragmentations as well as ·Bz-C(O)-peptide radical species. This result indicates that the duty cycle in the TEMPO-based FRIPS mass spectrometry can be reduced by one-half in the negative-ion mode. In addition, the fragment ions observed in the negative-ion experiments were mainly of the a-, c-, x-, and z-types, indicating that radical-driven tandem mass spectrometry was mainly responsible for the TEMPO-based FRIPS even with a single application of collisional activation. Furthermore, the survival fraction analysis of o-TEMPO-Bz-C(O)-peptides was made as a function of the applied normalized collision energy (NCE). This helped us to better understand the differences in FRIPS behavior between the positive- and negative-ion modes in terms of dissociation energetics. The duty-cycle improvement made in the present study provides a cornerstone for future research aiming to achieve a single-step FRIPS in the positive-ion mode.


Asunto(s)
Péptidos/química , Análisis de Secuencia de Proteína/métodos , Espectrometría de Masas en Tándem/métodos , Secuencia de Aminoácidos , Óxidos N-Cíclicos/química , Radicales Libres/química , Modelos Moleculares , Conformación Proteica
7.
Chemistry ; 19(1): 135-40, 2013 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-23172778

RESUMEN

Herein, we demonstrate a facile approach to manganese-doped highly ordered mesoporous silicate with oxidation-suppression function. As biocompatible supports of guest ions, the ordered mesoporous silicate was synthesized by evaporation-induced self-assembly. The phase-transition from disordered to lamellar structures in the highly ordered mesoporous structure of these porosity-tuned materials was controlled by adjusting the concentration of a lab-made polystyrene-b-polyethylene oxide copolymer. Manganese was successfully incorporated as a guest in the hexagonally packed mesoporous silicate by using an ultrasound-assisted technique. The incorporation of manganese ions into the pores of a mesoporous silicate support could be induced for host-guest functional applications. Manganese-doped mesoporous silicate structures have been examined for their use as antioxidizing agents by electron spin resonance (ESR) measurements and radical-scavenging tests. The manganese atoms in the mesoporous structures could act in a free-radical-scavenging capacity, much like manganese nanoparticles. The high efficiency of their oxidation-suppression function is extended for application to catalytic products.

8.
Rapid Commun Mass Spectrom ; 27(17): 1913-8, 2013 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-23939957

RESUMEN

RATIONALE: Isosorbide is a promising biomass-derived molecule that can be used as a replacement for fossil resource-derived diol monomers used in polyester synthesis. Due to its increased use in sustainable development, it is useful to understand the tandem mass spectrometric (MS/MS) fragmentation pathways of the isosorbide-based copolymer as an aid to interpreting the MS/MS spectra of other isosorbide-containing copolymers. METHODS: Collision-activated dissociation (CAD) experiments were performed on the sodiated/protonated molecules, [(AB)(n)A+Na(or H)](+), n = 2-5, of isosorbide (A)-1,4-cyclohexanedicarboxylic acid (B) oligomers formed by ion-trap electrospray ionization (ESI). RESULTS: Product ions arose from cleavage of the bonds between isosorbide and 1,4-cyclohexanedicarboxylic acid. In the MS/MS spectra, f(n)'' product ions were most abundant, followed by e(n) ions. McLafferty rearrangement appeared to provide the most facile pathway to yield the abundant f(n)'' and e(n) ions. In addition, a(n), b(n)'', f(n)''u(n)'', and en (+) ions were observed. Inductive cleavage and ß-elimination were suggested to be the pathways involved in generating e(n)(+)- and e(n)/b(n)''-type ions, respectively. CONCLUSIONS: Based on the obtained CAD spectra, the alternating sequences of two copolymer building blocks, A and B, were unambiguously determined. The fragmentation pathways leading to the observed product ion types were also established.


Asunto(s)
Ciclohexanos/química , Ácidos Dicarboxílicos/química , Isosorbida/química , Poliésteres/química , Espectrometría de Masas en Tándem/métodos , Estructura Molecular
9.
Bioorg Med Chem Lett ; 23(20): 5515-8, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-24012181

RESUMEN

A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopamine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC50=14 nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed inhibition (5.17 µM-85.6 nM) for three transporters.


Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación de Dopamina/síntesis química , Lactamas/química , Pirrolidinonas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores de Captación Adrenérgica/química , Inhibidores de Captación Adrenérgica/metabolismo , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/metabolismo , Humanos , Lactamas/síntesis química , Lactamas/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Unión Proteica , Pirrolidinonas/química , Pirrolidinonas/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo
10.
Bioorg Med Chem ; 21(17): 5480-7, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23810676

RESUMEN

In Parkinson's disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson's disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson's disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.


Asunto(s)
Inhibidores de la Monoaminooxidasa/uso terapéutico , Monoaminooxidasa/química , Oxazoles/química , Enfermedad de Parkinson/tratamiento farmacológico , Piridinas/química , Tiazoles/química , Sitios de Unión , Dominio Catalítico , Dopamina/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/patología , Piridinas/síntesis química , Piridinas/uso terapéutico , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-Actividad
11.
Biomed Pharmacother ; 165: 115139, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37454597

RESUMEN

TREK-1 (TWIK-related potassium channel-1) is a subunit of the two-pore domain potassium (K2p) channel and is widely expressed in the brain. TREK-1 knockout mice were shown to have antidepressant-like effects, providing evidence for the channel's potential as a therapeutic target. However, currently there is no good pharmacological inhibitor specifically targeting TREK-1 containing K2p channels that also displays similar antidepressant-like effects. Here, we sought to find selective and potent inhibitors for TREK-1 related dimers both in vitro and in vivo. We synthesized and evaluated 2-hydroxy-3-phenoxypropyl piperidine derivatives yielding a library from which many TREK-1 targeting candidates emerged. Among these, hydroxyl-phenyl- (2a), piperidino- (2g), and pyrrolidino- (2h) piperidinyl substituted compounds showed high potencies to TREK-1 homodimers with significant antidepressant-like effects in forced swim test and tail suspension test. Interestingly, these compounds were found to have high potencies to TWIK-1/TREK-1 heterodimers. Contrastingly, difluoropiperidinyl-4-fluorophenoxy (3e) and 4-hydroxyphenyl-piperidinyl-4-fluorophenoxy (3j) compounds had high potencies to TREK-1 homodimer but lower potency to TWIK-1/TREK-1 heterodimers without significant antidepressant-like effects. We observed positive correlation between inhibition potency to TWIK-1/TREK-1 and immobility time, and no correlation between inhibition potency to TREK-1 homodimer and immobility time. This was consistent with molecular docking simulations of selected compounds to TREK-1 homodimeric and TWIK-1/TREK-1 heterodimeric models. Existing antidepressant fluoxetine was also found to potently inhibit TWIK-1/TREK-1 heterodimers. Our study reveals novel potent TWIK-1/TREK-1 inhibitors 2a, 2g, and 2h as potential antidepressants and suggest that the TWIK-1/TREK-1 heterodimer could be a potential novel molecular therapeutic target for antidepressants.


Asunto(s)
Canales de Potasio de Dominio Poro en Tándem , Ratones , Animales , Simulación del Acoplamiento Molecular , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Encéfalo/metabolismo , Antidepresivos/farmacología , Ratones Noqueados
12.
Org Lett ; 24(48): 8870-8874, 2022 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-36414400

RESUMEN

A regioselective alkylation of ß,γ-alkynyl-α-imino esters by visible-light photocatalysis has been developed. This method enables 1,2-addition of methyl, primary, secondary, and tertiary alkyl radicals to the conjugated imines under mild conditions to produce a variety of quaternary alkynyl α-amino acid and cyclic amino acid motifs. Alkyl radicals are generated from alkyl bis(catecholato)silicates with an organic photocatalyst. This process is effective under an air atmosphere, providing operational benefits compared to conventional alkylation using organometallic reagents.

13.
Sci Rep ; 12(1): 9494, 2022 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-35680949

RESUMEN

A newly designed TEMPO-FRIPS reagent, 4-(2,2,6,6-tetramethylpiperidine-1-oxyl) methyl benzyl succinic acid N-hydroxysuccinimide ester or p-TEMPO-Bn-Sc-NHS, was synthesized to achieve single-step free radical-initiated peptide sequencing mass spectrometry (FRIPS MS) for a number of model peptides, including phosphopeptides. The p-TEMPO-Bn-Sc-NHS reagent was conjugated to target peptides, and the resulting peptides were subjected to collisional activation. The peptide backbone dissociation behaviors of the MS/MS and MS3 experiments were monitored in positive ion mode. Fragment ions were observed even at the single-step thermal activation of the p-TEMPO-Bn-Sc-peptides, showing mainly a-/x- and c-/z-type fragments and neutral loss ions. This confirms that radical-driven peptide backbone dissociations occurred with the p-TEMPO-Bn-Sc-peptides. Compared to the previous version of the TEMPO reagent, i.e., o-TEMPO-Bz-C(O)-NHS, the newly designed p-TEMPO-Bn-Sc-NHS has better conjugation efficiency for the target peptides owing to its improved structural flexibility and solubility in the experimental reagents. An energetic interpretation using the survival fraction as a function of applied normalized collision energy (NCE) ascertained the difference in the thermal activation between p-TEMPO-Bn-Sc- and o-TEMPO-Bz-C(O)- radical initiators. This study clearly demonstrates that the application of the p-TEMPO-Bn-Sc- radical initiator can improve the duty cycle, and this FRIPS MS approach has the potential to be implemented in proteomics studies, including phosphoproteomics.


Asunto(s)
Análisis de Secuencia de Proteína , Espectrometría de Masas en Tándem , Radicales Libres/química , Indicadores y Reactivos , Iones , Fosfopéptidos , Análisis de Secuencia de Proteína/métodos , Espectrometría de Masas en Tándem/métodos
14.
J Am Soc Mass Spectrom ; 33(3): 471-481, 2022 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-35099967

RESUMEN

TEMPO ((2,2,6,6-tetramethylpiperidine-1-yl)oxyl)-assisted free-radical-initiated peptide sequencing mass spectrometry (FRIPS MS) is applied to the top-down tandem mass spectrometry of guanidinated ubiquitin (UB(Gu)) ions, i.e., p-TEMPO-Bn-Sc-guanidinated ubiquitin (UBT(Gu)), to shed a light on gas-phase ubiquitin conformations. Thermal activation of UBT(Gu) ions produced protein backbone fragments of radical character, i.e., a-/x- and c-/z-type fragments. It is in contrast to the collision-induced dissociation (CID) results for UB(Gu), which dominantly showed the specific charge-remote CID fragments of b-/y-type at the C-terminal side of glutamic acid (E) and aspartic acid (D). The transfer of a radical "through space" was mainly observed for the +5 and +6 UBT(Gu) ions. This provides the information about folding/unfolding and structural proximity between the positions of the incipient benzyl radical site and fragmented sites. The analysis of FRIPS MS results for the +5 charge state ubiquitin ions shows that the +5 charge state ubiquitin ions bear a conformational resemblance to the native ubiquitin (X-ray crystallography structure), particularly in the central sequence region, whereas some deviations were observed in the unstable second structure region (ß2) close to the N-terminus. The ion mobility spectrometry results also corroborate the FRIPS MS results in terms of their conformations (or structures). The experimental results obtained in this study clearly demonstrate a potential of the TEMPO-assisted FRIPS MS as one of the methods for the elucidation of the overall gas-phase protein structures.


Asunto(s)
Óxidos N-Cíclicos/química , Análisis de Secuencia de Proteína/métodos , Espectrometría de Masas en Tándem/métodos , Ubiquitina/química , Radicales Libres/química , Modelos Moleculares , Ubiquitina/análisis
15.
Bioorg Med Chem Lett ; 21(10): 3002-6, 2011 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-21489792

RESUMEN

A serine-threonine kinase IKK-2 plays an important role in activation of NF-κB through phosphorylation of the inhibitor of NF-κB (IκB). As NF-κB is a major transcription factor that regulates genes responsible for cell proliferation and inflammation, development of selective IKK-2 inhibitors has been an important area of anti-inflammatory and anti-cancer research. In this study, to obtain active and selective IKK-2 inhibitors, various substituents were introduced to a piperidinyl aminopyrimidine core structure. The structure-activity relationship study indicated that hydrogen, methanesulfonyl, and aminosulfonyl groups substituted at the piperidinylamino functionality provide high inhibitory activity against IKK-2. Also, morpholinosulfonyl and piperazinosulfonyl group substituted at the aromatic ring attached to the aminopyrimidine core significantly increased the inhibitory activity of the resulting derivatives. In particular, compound 17 with the aromatic piperazinosulfonyl substituent showed the most potent (IC(50)=1.30 µM) and selective (over other kinases such as p38α, p38ß, JNK1, JNK2, JNK3, and IKK-1) inhibitory activity against IKK-2.


Asunto(s)
Descubrimiento de Drogas , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Piperidinas/química , Pirimidinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad
16.
J Am Chem Soc ; 132(42): 14706-9, 2010 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-20923158

RESUMEN

The functionalization and cross-linking of polyethylene is synthetically challenging, commonly relying on highly optimized radical based postpolymerization strategies. To address these difficulties, a norbornene monomer containing Meldrum's acid is shown to be effectively copolymerized with polyethylene using a nickel α-iminocarbaxamidato complex, providing high-melting, semicrystalline polymers with a tunable incorporation of the functional comonomer. Upon heating the copolymer to common polyethylene processing temperatures, the thermolysis of Meldrum's acid to ketene provides the desired reactive group. This simple and versatile methodology does not require small molecule radical sources or catalysts, and the dimerization of the in situ generated ketenes is shown to provide tunable cross-linking densities in polyethylene. Subsequent rheological and tensile experiments illustrate the ability to tune cross-linked polyethylene properties by comonomer incorporation and elucidate valuable structure/property relationships in these materials. This study illustrates the power of well-defined and synthetically accessible functional groups in polyolefin synthesis and functionalization.

17.
Analyst ; 134(8): 1706-12, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20448941

RESUMEN

Collisional activation of 2-[(2,2,6,6-tetramethylpiperidin-1-yloxy)methyl]benzoic acid (TEMPO-Bz)-conjugated peptide cations, prepared by attaching a TEMPO-derived precursor 1 to an N-terminal amino group or a lysine side chain, resulted in the formation of radical species. The subsequent tandem mass spectrometry on the radical cations exhibited odd-electron peptide backbone dissociations in the same manner as that observed by electron capture dissociation (ECD) or electron transfer dissociation (ETD). For example, a-, x-, or z-types of ions were major fragments and the disulfide bond was readily cleaved. The TEMPO-FRIPS (free radical initiated peptide sequencing) was also applicable to characterizing even singly protonated peptides, in contrast to ECD or ETD in which only doubly or highly protonated cations are responsive. The TEMPO-FRIPS approach also has universality in that it can be used in any type of a tandem mass spectrometer.


Asunto(s)
Secuencia de Aminoácidos , Óxidos N-Cíclicos/química , Radicales Libres/química , Gases/química , Péptidos/química , Transporte de Electrón/genética , Electrones , Iones , Péptidos/análisis , Espectrometría de Masa por Ionización de Electrospray/métodos
18.
J Am Soc Mass Spectrom ; 30(3): 538-547, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30414067

RESUMEN

Free radical-initiated peptide sequencing mass spectrometry (FRIPS MS) was employed to analyze a number of representative singly or doubly protonated phosphopeptides (phosphoserine and phosphotyrosine peptides) in positive ion mode. In contrast to collision-activated dissociation (CAD) results, a loss of a phosphate group occurred to a limited degree for both phosphoserine and phosphotyrosine peptides, and thus, localization of a phosphorylated site was readily achieved. Considering that FRIPS MS supplies a substantial amount of collisional energy to peptides, this result was quite unexpected because a labile phosphate group was conserved. Analysis of the resulting peptide fragments revealed the extensive production of a-, c-, x-, and z-type fragments (with some minor b- and y-type fragments), suggesting that radical-driven peptide fragmentation was the primary mechanism involved in the FRIPS MS of phosphopeptides. Results of this study clearly indicate that FRIPS MS is a promising tool for the characterization of post-translational modifications such as phosphorylation. Graphical Abstract.


Asunto(s)
Radicales Libres/química , Espectrometría de Masas/métodos , Fosfopéptidos/análisis , Fosfopéptidos/metabolismo , Óxidos N-Cíclicos/química , Fragmentos de Péptidos/análisis , Fosfopéptidos/química , Fosfoserina/análisis , Fosfotirosina/análisis , Procesamiento Proteico-Postraduccional , Protones
19.
J Phys Chem B ; 112(15): 4735-40, 2008 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-18366215

RESUMEN

We investigated the structures of ionic liquids (1-butyl-3-methylimidazolium iodide [BMIM][I] and 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4]) and their aqueous mixtures using attenuated total reflection (ATR) infrared absorption and Raman spectroscopy. The ATR spectrum in the CHx (x = 1, 2, 3) vibration region from 2800 to 3200 cm-1 was very different between [BMIM][BF4] and [BMIM][I] even though all the spectral features in this region were from the butyl chain and the imidazolium ring of the same cation. The spectrum did not change appreciably irrespective of the water concentration for [BMIM][BF4], whereas the spectrum from [BMIM][I] showed significant changes as the water concentration was increased, especially in CH-vibration modes from the imidazolium ring. For very diluted solutions both aqueous mixtures of [BMIM][I] and [BMIM][BF4] showed very similar spectra. Mixing of [BMIM][I] with heavy water (D2O) facilitated the isotopic exchange of the proton attached to the most acidic carbon of the imidazolium ring into deuterium from D2O, whereas even prolonged exposure to D2O did not induce any isotopic exchange for [BMIM][BF4]. Raman spectra around 600 cm(-1) indicative of the butyl chain conformation also changed differently as the water concentration was increased between [BMIM][I] and [BMIM][BF4]. These differences are considered to come from the variation in the position of the anion, where I- is expected to be closer to the C(2) hydrogen of the imidazolium cation and interacting more specifically as compared to BF(4-).


Asunto(s)
Boratos/química , Imidazoles/química , Líquidos Iónicos/química , Aniones/química , Óxido de Deuterio/química , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Estructura Molecular , Espectrofotometría Infrarroja/métodos , Espectrometría Raman/métodos , Vibración , Agua/química
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