Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros

Bases de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Adv Mater ; 35(19): e2210363, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36787500

RESUMEN

Hypoxia represents a remarkably exploitable target for cancer therapy, is encountered only in solid human tumors, and is highly associated with cancer resistance and recurrence. Here, a hypoxia-activated mitochondria-accumulated Ru(II) polypyridyl prodrug functionalized with conjugated azo (Az) and nitrogen mustard (NM) functionalities, RuAzNM, is reported. This prodrug has multimodal theranostic properties toward hypoxic cancer cells. Reduction of the azo group in hypoxic cell microenvironments gives rise to the generation of two primary amine products, a free aniline mustard, and the polypyridyl RuNH2 complex. Thus, the aniline mustard triggers generation of reactive oxygen species (ROS) and mtDNA crosslinking. Meanwhile, the resultant biologically benign phosphorescent RuNH2 gives rise to a diagnostic signal and signals activation of the phototherapy. This multimodal therapeutic effect eventually elevates ROS levels, depletes reduced nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP), and induces mitochondrial membrane damage, mtDNA damage, and ultimately cell apoptosis. This unique strategy allows controlled multimodal theranostics to be realized in hypoxic cells and multicellular spheroids, making RuAzNM a highly selective and effective cancer-cell-selective theranostic agent (IC50  = 2.3 µm for hypoxic HepG2 cancer cells vs 58.2 µm for normoxic THL-3 normal cells). This is the first report of a metal-based compound developed as a multimodal theranostic agent for hypoxia.


Asunto(s)
Mostaza de Anilina , Antineoplásicos , Neoplasias , Profármacos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Profármacos/farmacología , Profármacos/uso terapéutico , Hipoxia/metabolismo , ADN Mitocondrial , Oxidación-Reducción , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico
2.
Nat Chem ; 11(11): 1041-1048, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31548671

RESUMEN

Hypoxic tumours are a major problem for cancer photodynamic therapy. Here, we show that photoredox catalysis can provide an oxygen-independent mechanism of action to combat this problem. We have designed a highly oxidative Ir(III) photocatalyst, [Ir(ttpy)(pq)Cl]PF6 ([1]PF6, where 'ttpy' represents 4'-(p-tolyl)-2,2':6',2''-terpyridine and 'pq' represents 3-phenylisoquinoline), which is phototoxic towards both normoxic and hypoxic cancer cells. Complex 1 photocatalytically oxidizes 1,4-dihydronicotinamide adenine dinucleotide (NADH)-an important coenzyme in living cells-generating NAD• radicals with a high turnover frequency in biological media. Moreover, complex 1 and NADH synergistically photoreduce cytochrome c under hypoxia. Density functional theory calculations reveal π stacking in adducts of complex 1 and NADH, facilitating photoinduced single-electron transfer. In cancer cells, complex 1 localizes in mitochondria and disrupts electron transport via NADH photocatalysis. On light irradiation, complex 1 induces NADH depletion, intracellular redox imbalance and immunogenic apoptotic cancer cell death. This photocatalytic redox imbalance strategy offers a new approach for efficient cancer phototherapy.


Asunto(s)
Citocromos c/metabolismo , Neoplasias/metabolismo , Hipoxia Tumoral , Antineoplásicos/química , Antineoplásicos/farmacología , Biocatálisis , Muerte Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Teoría Funcional de la Densidad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Conformación Molecular , NAD/antagonistas & inhibidores , NAD/metabolismo , Neoplasias/patología , Oxidación-Reducción , Procesos Fotoquímicos , Hipoxia Tumoral/efectos de los fármacos
3.
Acta Crystallogr C Struct Chem ; 75(Pt 3): 271-276, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30833521

RESUMEN

The molecular structure of the anti-aging agent J147 [systematic name: (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-(3-methoxybenzylidene)acetohydrazide], C18H17F3N2O2, has been determined at 150 K. The crystal structure corresponds to the minimum-energy conformation in the gas phase calculated by density functional theory (DFT). 15 other conformations have been calculated and compared with the minimum, denoted 1111. NMR spectroscopic data have been obtained and compared with those from Gauge Independent Atomic Orbital (GIAO) calculations. DFT calculations allow the reduction of the 16 possible rotamers to the four most stable (i.e. 1111, 1112, 1121 and 1222); in addition, the calculated barriers connecting these minima are low enough to permit their interconversion. Comparison of the NMR spectroscopic results, both experimental and calculated, point to the 1121 isomer being present in chloroform solution.


Asunto(s)
Curcumina/análogos & derivados , Fármacos Neuroprotectores/química , Curcumina/síntesis química , Curcumina/química , Teoría Funcional de la Densidad , Modelos Químicos , Conformación Molecular , Fármacos Neuroprotectores/síntesis química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA