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1.
Molecules ; 29(12)2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38930915

RESUMEN

Organic arsenic compounds such as p-aminophenylarsine oxide (p-APAO) are easier for structural optimization to improve drug-like properties such as pharmacokinetic properties, therapeutic efficacy, and target selectivity. In order to strengthen the selectivity of 4-(1,3,2-dithiarsinan-2-yl) aniline 7 to tumor cell, a thiourea moiety was used to strengthen the anticancer activity. To avoid forming a mixture of α/ß anomers, the strategy of 2-acetyl's neighboring group participation was used to lock the configuration of 2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isothiocyanate from 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide. 1-(4-(1,3,2-dithiarsinan-2-yl) aniline)-2-N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranos-1-yl)-thiourea 2 can increase the selectivity of human colon cancer cells HCT-116 (0.82 ± 0.06 µM vs. 1.82 ± 0.07 µM) to human embryonic kidney 293T cells (1.38 ± 0.01 µM vs. 1.22 ± 0.06 µM) from 0.67 to 1.68, suggesting a feasible approach to improve the therapeutic index of arsenic-containing compounds as chemotherapeutic agents.


Asunto(s)
Antineoplásicos , Diseño de Fármacos , Tiourea , Humanos , Tiourea/química , Tiourea/farmacología , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Glucosa/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HCT116 , Estructura Molecular , Arsenicales/química , Arsenicales/farmacología , Arsenicales/síntesis química , Relación Estructura-Actividad
2.
J Nat Prod ; 83(9): 2809-2813, 2020 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-32830503

RESUMEN

Arsinothricin [AST (1)], a new broad-spectrum organoarsenical antibiotic, is a nonproteinogenic analogue of glutamate that effectively inhibits glutamine synthetase. We report the chemical synthesis of an intermediate in the pathway to 1, hydroxyarsinothricin [AST-OH (2)], which can be converted to 1 by enzymatic methylation catalyzed by the ArsM As(III) S-adenosylmethionine methyltransferase. This is the first report of semisynthesis of 1, providing a source of this novel antibiotic that will be required for future clinical trials.


Asunto(s)
Antibacterianos/síntesis química , Arsenicales/síntesis química , Antibacterianos/farmacología , Arsenicales/farmacología , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/farmacología , Glutamato-Amoníaco Ligasa/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , S-Adenosilmetionina/antagonistas & inhibidores
3.
ChemMedChem ; 15(6): 552-558, 2020 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-32101363

RESUMEN

Based on the potential therapeutic value in targeting mitochondria and the fluorophore tracing ability, a fluorescent mitochondria-targeted organic arsenical PDT-PAO-F16 was fabricated, which not only visualized the cellular distribution, but also exerted anti-cancer activity in vitro and in vivo via targeting pyruvate dehydrogenase complex (PDHC) and respiratory chain complexes in mitochondria. In details, PDT-PAO-F16 mainly accumulated into mitochondria within hours and suppressed the activity of PDHC resulting in the inhibition of ATP synthesis and thermogenesis disorder. Moreover, the suppression of respiratory chain complex I and IV accelerated the mitochondrial dysfunction leading to caspase family-dependent apoptosis. In vivo, the acute promyelocytic leukemia was greatly alleviated in the PDT-PAO-F16 treated group in APL mice model. Our results demonstrated the organic arsenical precursor with fluorescence imaging and target-anticancer efficacy is a promising anticancer drug.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arsenicales/farmacología , Transporte de Electrón/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Complejo Piruvato Deshidrogenasa/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Arsenicales/síntesis química , Arsenicales/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Complejo Piruvato Deshidrogenasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo
4.
Int J Mol Sci ; 20(24)2019 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-31835667

RESUMEN

Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1α and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.


Asunto(s)
Arsenicales/farmacología , Progresión de la Enfermedad , Lactato Deshidrogenasa 5/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Compuestos Orgánicos/farmacología , Animales , Arsenicales/síntesis química , Arsenicales/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Femenino , Glutatión/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Lactato Deshidrogenasa 5/antagonistas & inhibidores , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Compuestos Orgánicos/síntesis química , Compuestos Orgánicos/química , Consumo de Oxígeno/efectos de los fármacos , Complejo Piruvato Deshidrogenasa/metabolismo , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Tiorredoxinas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Am Chem Soc ; 141(48): 18958-18963, 2019 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-31744291

RESUMEN

Herein we report a direct vicinal difunctionalization of thiophenes via the palladium/norbornene (Pd/NBE) cooperative catalysis. A series of mono- and disubstituted thiophenes can be difunctionalized site-selectively and regioselectively at the C4 and C5 positions in good yields, enabled by an arsine ligand and a unique amide-based NBE. The synthetic utility has been shown in derivatizations of complex bioactive compounds and an open-flask gram-scale preparation. Preliminary results have been obtained in the difunctionalization of furans and a direct C4-selective arylation of 2-substituted thiophenes.


Asunto(s)
Norbornanos/química , Paladio/química , Tiofenos/química , Arsenicales/síntesis química , Arsenicales/química , Catálisis , Furanos/síntesis química , Furanos/química , Norbornanos/síntesis química , Estereoisomerismo , Tiofenos/síntesis química
6.
Chemosphere ; 233: 946-953, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31340422

RESUMEN

Scorodite is an important mineral not only for arsenic (As) removal from industrial wastewaters but also in the mobility and final fate of As in waste rocks, contaminated soils and sediments, and mine tailings. Because of the mineral's high As-loading capacity and stability, numerous studies have been done to understand its formation. Unfortunately, most of these studies were limited to elevated temperatures (>70 °C), so the processes involved in scorodite formation under ambient conditions remain unclear. This study provides evidence of the catalytic effects of hematite on the formation of scorodite at 25 °C in a pyrite-rich natural geologic material. Scorodite peaks were detected in the XRD patterns of the leaching residues with and without hematite, but those in the former were stronger and more pronounced than the latter. These results suggest that the formation of scorodite was catalysed by hematite, a generalisation that is further supported by strong characteristic IR absorption bands of scorodite at 819 cm-1 (As-O bending vibration), 785 and 725 cm-1 (As-O stretching vibrations), and 2990 cm-1 (OH-vibration) as well as the distinct XPS binding energies of Fe(III)-As (709.7 eV), As(V)-O (44.8, 44.31 and 43.7 eV), O2- (530.5 eV) and coordinated water (531.3 eV) in scorodite. This phenomenon could be attributed to three possible mechanisms: (1) more rapid precipitation promoted by the "seeding" effect of hematite particles, (2) additional supply of Fe3+ from hematite dissolution under acidic conditions, and (3) enhanced oxidations of Fe2+ to Fe3+ and As(III) to As(V) on the surface of hematite.


Asunto(s)
Arsénico/química , Arsenicales/síntesis química , Compuestos Férricos/química , Aguas Residuales/química , Purificación del Agua/métodos , Catálisis , Hierro/química , Oxidación-Reducción , Contaminantes del Suelo/análisis , Sulfuros/química , Contaminantes Químicos del Agua/análisis
7.
Bioorg Med Chem ; 27(5): 760-768, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30665675

RESUMEN

Considering the vital role of mitochondria in the anti-cancer mechanism of organic arsenical, the mitochondria-targeted precursor PDT-PAO-TPP was designed and synthesized. PDT-PAO-TPP, as a delocalization lipophilic cation (DLCs) which mainly accumulated in mitochondria, contributed to improve anti-cancer efficacy and selectivity towards NB4 cells. In detail, PDT-PAO-TPP inhibited the activity of PDHC resulting in the suppression of ATP synthesis and thermogenesis disorder. Additionally, the inhibition of respiratory chain complex I and IV by short-time incubation of PDT-PAO-TPP also accelerated the respiration dysfunction and continuous generation of ROS. These results led to the release of cytochrome c and activation of caspase family-dependent apoptosis. Different from the mechanism of PDT-PAO in HL-60 cells, it mainly induced the mitochondrial metabolic disturbance resulting in the intrinsic apoptosis via inhibiting the activity of PDHC in NB4 cells, which also implied that the efficacy exertion of organic arsenical was a complex process involved in many aspects of cellular function. This study systematically clarifies the anti-cancer mechanism of mitochondria-targeted organic arsenical PDT-PAO-TPP and confirms the new target PDHC of organic arsenicals, which further supports the organic arsenical as a promising anticancer drug.


Asunto(s)
Antineoplásicos/farmacología , Arsenicales/farmacología , Mitocondrias/efectos de los fármacos , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Arsenicales/síntesis química , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , Citocromos c/metabolismo , Humanos , Membranas Mitocondriales/metabolismo , Permeabilidad/efectos de los fármacos , Complejo Piruvato Deshidrogenasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Termogénesis/efectos de los fármacos
8.
Eur J Med Chem ; 143: 1090-1102, 2018 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-29150332

RESUMEN

Considering the vital role of cellular redox state, more and more researches focus on the design of drugs targeting thioredoxin reductase (TrxR), an important enzyme in maintaining the balance of cellular redox. Here two organic arsenicals, 2-(((4-(1,3,2-dithiarsinan-2-yl) phenyl) imino) methyl) phenol (PIM-PAO-PDT) and N-(4-(1,3,2-dithiarsinan-2-yl) phenyl)-2-hydroxybenzamide (PAM-PAO-PDT), bearing the S-As-S chemical scaffold and different linking groups have been synthesized, and both of them show the better inhibitory activity and selectivity towards HL-60 cells. Importantly, it is illustrated that they can target TrxR selectively and inhibit its activity via the disturbance for Cys83 and Cys88 located in conserved active sites. Afterwards, the cells suffer from the burst of ROS, consumption of antioxidants and high sensitivity for oxidants, which further damage the mitochondria leading to dysfunction including the collapse of membrane potential, ATP level decline, mitochondrial membrane swelling, MPTP opening, Ca2+ and cytochrome c release. Then the mitochondria-dependent apoptosis is triggered by PIM-PAO-PDT and PAM-PAO-PDT, which can also be deterred in the presence of NAC, DTT or LA. Although the organic arsenicals can suppress TrxR activity, the following oxidative stress and mitochondrial dysfunction are the main causes for apoptosis.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arsenicales/farmacología , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Arsenicales/síntesis química , Arsenicales/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Mitocondrias/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Células Tumorales Cultivadas
9.
Anal Chem ; 89(21): 11203-11207, 2017 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-29057653

RESUMEN

Mitochondrial vicinal dithiol-containing proteins (VDPs) are key regulators in cellular redox homeostasis and useful markers for diagnostics of redox-dependent diseases. Current probes fail to target mitochondrial VDPs and show limited sensitivity and response rate. We develop a novel fluorescent probe using an engineered benzoxadiazole fluorophore that allows selective targeting of mitochondria and exhibits highly sensitive environment responsiveness. This probe is almost nonfluorescent in aqueous media, while delivering intense fluorescence upon binding to VDPs via a cyclic dithiaarsane ligand. The fluorescence probe is shown to have rapid response within 30 s and high sensitivity for detecting reduced bovine serum albumin (rBSA) in the concentration range from 0 to 0.1 µM with a detection limit of 2 nM. To our knowledge, this is the first fluorescence probe for VDPs which exhibits deep red emission, instantaneous response, high turn-on fluorescence ratio, and specific mitochondrial localization. It may provide a new tool for in situ monitoring mitochondrial VDPs.


Asunto(s)
Arsenicales/química , Cisteína/química , Colorantes Fluorescentes/química , Mitocondrias/metabolismo , Oxadiazoles/química , Proteínas/análisis , Animales , Arsenicales/síntesis química , Bovinos , Colorantes Fluorescentes/síntesis química , Humanos , Límite de Detección , Células MCF-7 , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Oxadiazoles/síntesis química , Albúmina Sérica Bovina/análisis
10.
Sci Rep ; 7(1): 11548, 2017 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-28912556

RESUMEN

In the light of the promising bioactivity of the tetraarsenic marine metabolite arsenicin A, the dimethyl analogue 2 and four isomeric methylene homologues (including the natural product itself) were obtained using a one-pot microwave-assisted synthesis, starting from arsenic (III) oxide. Due to the poor diagnostic value of the NMR technique in the structural elucidation of these molecules, they were fully characterized by mass spectrometry and infrared (IR)-spectroscopy, comparing density functional theory (DFT) simulated and experimental spectra. This synthetic procedure provided a fast and efficient access to the cytotoxicity evaluation of organoarsenical leads of the natural hit molecule. From in vitro screening, each tested compound resulted in being more active than the FDA-approved arsenic trioxide, with the most lipophilic molecule in the series showing the best growth inhibition of both leukemia and solid tumor cell lines. These results may open promising perspectives in the development of new more potent and selective arsenical drugs against solid tumors.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Arsenicales/síntesis química , Arsenicales/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Espectrometría de Masas , Estructura Molecular , Espectrofotometría Infrarroja
11.
J Inorg Biochem ; 168: 67-75, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28013066

RESUMEN

The antileukemic activity, mechanisms and serum albumin interactions of an arsenomolybdate, K2Na[AsMo6O21(O2CCH2NH3)3]·6H2O (1), was evaluated in the human leukemia HL-60 and U937 cells. The results indicated that 1 could inhibit the proliferation of both leukemia cell lines in a dose-dependent manner with the 50% lethal concentration (IC50) value of 8.61µM for HL-60 and 14.50µM for U937 at 24h, compare to the positive controls, all-trans retinoic acid (ATRA) with IC50 value of 20.76µM and 14.85µM,and As2O3 with IC50 value of 6.40µM and 8.75µM at 24h, respectively (P<0.05). Furthermore, the anti-leukemia activity of compound 1 might be medicated by arresting the leukemic cells in the G1 phase and inducing apoptosis via caspase-3 and bcl-2 regulatory proteins. Spectroscopic techniques results showed that the fluorescence of human serum albumin was quenched by compound 1, and the quenching mechanism was mainly static quenching. Compound 1 might be a potential medicinal candidate against acute promyelocytic leukemia.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arsenicales/farmacología , Caspasa 3/efectos de los fármacos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Molibdeno/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Arsenicales/síntesis química , Arsenicales/química , Western Blotting , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Estabilidad de Medicamentos , Citometría de Flujo , Fluorescencia , Células HL-60 , Humanos , Concentración 50 Inhibidora , Molibdeno/química , Células U937
12.
Nat Commun ; 7: 12749, 2016 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-27834371

RESUMEN

With the emergence of applications based on short-wavelength infrared light, indium arsenide quantum dots are promising candidates to address existing shortcomings of other infrared-emissive nanomaterials. However, III-V quantum dots have historically struggled to match the high-quality optical properties of II-VI quantum dots. Here we present an extensive investigation of the kinetics that govern indium arsenide nanocrystal growth. Based on these insights, we design a synthesis of large indium arsenide quantum dots with narrow emission linewidths. We further synthesize indium arsenide-based core-shell-shell nanocrystals with quantum yields up to 82% and improved photo- and long-term storage stability. We then demonstrate non-invasive through-skull fluorescence imaging of the brain vasculature of murine models, and show that our probes exhibit 2-3 orders of magnitude higher quantum yields than commonly employed infrared emitters across the entire infrared camera sensitivity range. We anticipate that these probes will not only enable new biomedical imaging applications, but also improved infrared nanocrystal-LEDs and photon-upconversion technology.


Asunto(s)
Arsenicales/síntesis química , Encéfalo/diagnóstico por imagen , Nanopartículas del Metal/química , Puntos Cuánticos/química , Animales , Indio , Rayos Infrarrojos , Ratones , Imagen Óptica
13.
Angew Chem Int Ed Engl ; 55(45): 14051-14056, 2016 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-27723242

RESUMEN

Identification of arsenic-binding proteins is important for understanding arsenic health effects and for developing arsenic-based therapeutics. We report here a strategy for the capture and identification of arsenic-binding proteins in living cells. We designed an azide-labeled arsenical, p-azidophenylarsenoxide (PAzPAO), to serve bio-orthogonal functions: the trivalent arsenical group binds to cellular proteins in situ, and the azide group facilitates click chemistry with dibenzylcyclooctyne. The selective and efficient capture of arsenic-binding proteins enables subsequent enrichment and identification by shotgun proteomics. Applications of the technique are demonstrated using the A549 human lung carcinoma cells and two in vitro model systems. The technique enables the capture and identification of 48 arsenic-binding proteins in A549 cells incubated with PAzPAO. Among the identified proteins are a series of antioxidant proteins (e.g., thioredoxin, peroxiredoxin, peroxide reductase, glutathione reductase, and protein disulfide isomerase) and glyceraldehyde-3-phosphate dehydrogenase. Identification of these functional proteins, along with studies of arsenic binding and enzymatic inhibition, points to these proteins as potential molecular targets that play important roles in arsenic-induced health effects and in cancer treatment.


Asunto(s)
Arsénico/análisis , Arsenicales/química , Azidas/química , Proteínas Portadoras/análisis , Arsenicales/síntesis química , Azidas/síntesis química , Línea Celular Tumoral , Química Clic , Humanos , Modelos Moleculares , Estructura Molecular
14.
Inorg Chem ; 55(16): 8091-8, 2016 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-27453472

RESUMEN

Arsenic-72 ((72)As) and (77)As have nuclear properties useful for positron emission tomography (PET) and radiotherapy, respectively. The thiophilic nature of arsenic led to the evaluation of dithioarylarsines for potential use in radiopharmaceuticals. Several dithioarylarsines were synthesized from their arylarsonic acids and dithiols and were fully characterized by NMR, ESI-MS, and X-ray crystallography. This chemistry was translated to the no-carrier-added (nca) (77)As level. Because arsenic was available at the nca nanomolar level only as [(77)As]arsenate, this required addition of an aryl group directly to the As to form the [(77)As]arylarsonic acid. The [(77)As]arsenate was reduced from (77)As (V) to (77)As (III), and a modified Bart reaction was used to incorporate the aryl ring onto the (77)As, which was followed by dithiol addition. Various modifications and optimizations resulted in 95% radiochemical yield of nca [(77)As]p-ethoxyphenyl-1,2-ethanedithiolatoarsine.


Asunto(s)
Arsenicales/química , Radiofármacos/química , Arsenicales/síntesis química , Técnicas de Química Sintética , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Estructura Molecular , Radiofármacos/síntesis química , Espectrometría de Masa por Ionización de Electrospray , Tolueno/análogos & derivados , Tolueno/química
15.
Arch Pharm (Weinheim) ; 349(4): 233-41, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26948688

RESUMEN

Two photo-crosslinking biarsenical (CrAsH-EDT2 )-modified probes were synthesized that are expected to be useful tools for tetracysteine-labeled proteins to facilitate the co-affinity purification of their DNA binding sequences and interacting proteins. In addition, improvements for the synthesis of CrAsH-EDT2 and N(1) -(4-azido-2-nitrophenyl)hexane-1,6-diamine are reported. Both photoprobes effectively entered HeLa cells (and the nucleus) and were dependent on the tetracysteine motif in recombinant DMRT1 (doublesex and Mab3-related transcription factor) to induce fluorescence, suggesting that their crosslinking abilities can be exploited for the identification of nucleic acids and proteins associated with a protein of interest.


Asunto(s)
Arsénico , Arsenicales/química , Azidas/química , Reactivos de Enlaces Cruzados/química , Diaminas/química , Diazometano/análogos & derivados , Diazometano/química , Fluoresceínas/química , Mercaptoetanol/análogos & derivados , Etiquetas de Fotoafinidad/química , Arsenicales/síntesis química , Azidas/síntesis química , Diaminas/síntesis química , Diazometano/síntesis química , Fluoresceínas/síntesis química , Células HeLa , Humanos , Mercaptoetanol/química , Etiquetas de Fotoafinidad/síntesis química , Relación Estructura-Actividad , Factores de Transcripción/metabolismo
16.
J Am Chem Soc ; 137(12): 4215-22, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25794267

RESUMEN

The entropy-driven affinity of trivalent (in)organic arsenicals for closely spaced dithiols has been exploited to develop a novel route to peptide/protein-polymer conjugation. A trivalent arsenous acid (As(III)) derivative (1) obtained from p-arsanilic acid (As(V)) was shown to readily undergo conjugation to the therapeutic peptide salmon calcitonin (sCT) via bridging of the Cys(1)-Cys(7) disulfide, which was verified by RP-HPLC and MALDI-ToF-MS. Conjugation was shown to proceed rapidly (t < 2 min) in situ and stoichiometrically through sequential reduction-conjugation protocols, therefore exhibiting conjugation efficiencies equivalent to those reported for the current leading disulfide-bond targeting strategies. Furthermore, using bovine serum albumin as a model protein, the trivalent organic arsenical 1 was found to demonstrate enhanced specificity for disulfide-bond bridging in the presence of free cysteine residues relative to established maleimide functional reagents. This specificity represents a shift toward potential orthogonality, by clearly distinguishing between the reactivity of mono- and disulfide-derived (vicinal or neighbors-through-space) dithiols. Finally, p-arsanilic acid was transformed into an initiator for aqueous single electron-transfer living radical polymerization, allowing the synthesis of hydrophilic arsenic-functional polymers which were shown to exhibit negligible cytotoxicity relative to a small molecule organic arsenical, and an unfunctionalized polymer control. Poly(poly[ethylene glycol] methyl ether acrylate) (PPEGA480, DPn = 10, Mn,NMR = 4900 g·mol(-1), D = 1.07) possessing a pentavalent arsenic acid (As(V)) α-chain end was transformed into trivalent As(III) post-polymerization via initial reduction by biological reducing agent glutathione (GSH), followed by binding of GSH. Conjugation of the resulting As(III)-functional polymer to sCT was realized within 35 min as indicated by RP-HPLC and verified later by thermodynamically driven release of sCT, from the conjugate, in the presence of strong chelating reagent ethanedithiol.


Asunto(s)
Arsenicales/química , Calcitonina/química , Cisteína/química , Acrilatos/química , Animales , Arsenicales/síntesis química , Arsenitos/síntesis química , Arsenitos/química , Línea Celular , Ratones , Modelos Moleculares , Polietilenglicoles/química , Polimerizacion , Salmón , Compuestos de Sulfhidrilo/química
17.
Org Lett ; 16(14): 3824-7, 2014 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-24999741

RESUMEN

There is great interest in fluorogenic compounds that tag biomolecules within cells. Biarsenicals are fluorogenic compounds that become fluorescent upon binding four proximal Cys thiols, a tetracysteine (Cys(4)) motif. This work details interactions between the biarsenical AsCy3 and Cys(4) peptides. Maximal affinity was observed when two Cys-Cys pairs were separated by at least 8 amino acids; the highest affinity ligand bound in the nanomolar concentration range (K(app) = 43 nM) and with a significant (3.2-fold) fluorescence enhancement.


Asunto(s)
Arsenicales/síntesis química , Cisteína/química , Colorantes Fluorescentes/química , Péptidos/química , Arsenicales/química , Dipéptidos/química , Ligandos , Estructura Molecular , Estructura Terciaria de Proteína
18.
J Med Chem ; 57(12): 5203-11, 2014 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-24867309

RESUMEN

The selenoprotein thioredoxin reductase (TrxR) plays a pivotal role in regulating cellular redox homeostasis and has attracted increasing attention as a promising anticancer drug target. We report here that 2-(4-aminophenyl)-1,3,2-dithiarsinane (PAO-PDT, 4), a potent and highly selective small molecule inhibitor of TrxR, stoichiometrically binds to the C-terminal selenocysteine/cysteine pair in the enzyme in vitro and induces oxidative stress-mediated apoptosis in HL-60 cells. The molecular action of 4 in cells involves inhibition of TrxR, elevation of reactive oxygen species, depletion of cellular thiols, and activation of caspase-3. Knockdown of TrxR sensitizes the cells to 4 treatment, whereas overexpression of the functional enzyme alleviates the cytotoxicity, providing physiological relevance for targeting TrxR by 4 in cells. The simplicity of the structure and the presence of an easily manipulated amine group will facilitate the further development of 4 as a potential cancer chemotherapeutic agent.


Asunto(s)
Antineoplásicos/síntesis química , Apoptosis , Arsenicales/síntesis química , Estrés Oxidativo , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Arsenicales/química , Arsenicales/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Técnicas de Silenciamiento del Gen , Células HL-60 , Humanos , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Reductasa de Tiorredoxina-Disulfuro/genética , Reductasa de Tiorredoxina-Disulfuro/metabolismo
19.
J Hazard Mater ; 264: 481-9, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-24238807

RESUMEN

A novel polyaniline based composite cation exchange material has been synthesized by simple chemical route and characterized on the basis of sophisticated techniques. XRD and SEM analyses reveal the amorphous morphology of the material. The partition coefficient studies of different metal ions on the material were performed in DMW and diverse concentrations of HClO4 solutions. On the basis of high Kd values some significant separations of heavy toxic metal ions were achieved from synthetic mixtures as well as tap water samples by using columns of this exchanger. For the optimum adsorption of dye on the material, the effect of various parameters along with Langmuir and Freundlich adsorption isotherm were examined. The observed result of conducting measurement indicates that the material covers semiconductor range. The photochemical degradation of industrial dyes and antimicrobial activity were also investigated which show significant results than some of the known antibiotics. On the basis of good ion exchange capacity along with photochemical degradation and microbial activity, polyanilineTi(IV)arsenophosphate can be considered as an excellent conducting material for the treatment metal ions and degradation of organic pollutants.


Asunto(s)
Antiinfecciosos/síntesis química , Arsenicales/síntesis química , Complejos de Coordinación/síntesis química , Contaminantes Químicos del Agua/química , Adsorción , Colorantes/química , Conductividad Eléctrica , Metales Pesados/análisis , Fotólisis
20.
J Hazard Mater ; 262: 25-30, 2013 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24007995

RESUMEN

Diphenylarsinic acid (DPAA) is a toxic phenylarsenical compound often found around sites contaminated with phenylarsenic chemical warfare agents, diphenylcyanoarsine or diphenylchloroarsine, which were buried in soil after the World Wars. This research concerns the elucidation of the chemical structure of an arsenic metabolite transformed from DPAA under anaerobic sulfate-reducing soil conditions. In LC/ICP-MS analysis, the retention time of the metabolite was identical to that of a major phenylarsenical compound synthesized by chemical reaction of DPAA and hydrogen sulfide. Moreover the mass spectra for the two compounds measured using LC/TOF-MS were similar. Subsequent high resolution mass spectral analysis indicated that two major ions at m/z 261 and 279, observed on both mass spectra, were attributable to C12H10AsS and C12H12AsSO, respectively. These findings strongly suggest that the latter ion is the molecular-related ion ([M+H](+)) of diphenylthioarsinic acid (DPTA; (C6H5)2AsS(OH)) and the former ion is its dehydrated fragment. Thus, our results reveal that DPAA can be transformed to DPTA, as a major metabolite, under sulfate-reducing soil conditions. Moreover, formation of diphenyldithioarsinic acid and subsequent dimerization were predicted by the chemical reaction analysis of DPAA with hydrogen sulfide. This is the first report to elucidate the occurrence of DPAA-thionation in an anaerobic soil.


Asunto(s)
Arsenicales/química , Arsenicales/síntesis química , Contaminantes del Suelo/química , Sulfatos/química , Anaerobiosis , Cromatografía Líquida de Alta Presión , Espectrometría de Masa por Ionización de Electrospray
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