RESUMEN
Near-infrared (NIR)-absorbing organic small molecules hold great promise as the phototheranostic agents for clinical translation by virtue of their intrinsic advantages such as well-defined chemical structure, high purity, and good reproducibility. However, most of the currently available ones face the challenges in varying degrees in terms of photothermal instability, and photobleaching/reactive oxygen nitrogen species (RONS) inresistance, which indeed impair their practical applications in precise diagnosis and treatment of diseases. Herein, we developed highly stable and biocompatible organic nanoparticles (ONPs) for effective phototheranostic application by design and synthesis of an organic small molecule (namely TPA-T-TQ) with intensive absorption in the NIR window. The TPA-T-TQ ONPs with no noticeable in vivo toxicity possess better capacities in photothermal conversion and photoacoustic imaging (PAI), as well as show far higher stabilities including thermal/photothermal stabilities, and photobleaching/RONS resistances, when compared with the clinically popularly used indocyanine green. Thanks to the combined merits, the ONPs can serve as an efficient probe for in vivo PAI in a high-contrast manner, which also significantly causes the stoppage of tumor growth in living mice through PAI-guided photothermal therapy. This study thus provides an insight into the development of advanced NIR-absorbing small molecules for practical phototheranostic applications.
Asunto(s)
Nanopartículas/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Quinoxalinas/uso terapéutico , Compuestos de Terfenilo/uso terapéutico , Nanomedicina Teranóstica/métodos , Tiadiazoles/uso terapéutico , Aminas/química , Aminas/uso terapéutico , Animales , Femenino , Hipertermia Inducida/métodos , Rayos Infrarrojos , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Quinoxalinas/química , Compuestos de Terfenilo/química , Tiadiazoles/químicaRESUMEN
Within a project focusing on the chemopreventive potential of algal phenols, two phloroglucinol derivatives, belonging to the class of fucophlorethols, and the known fucotriphlorethol A were obtained from the ethanolic extract of the brown alga Fucus vesiculosus L. The compounds trifucodiphlorethol A and trifucotriphlorethol A are composed of six and seven units of phloroglucinol, respectively. The compounds were examined for their cancer chemopreventive potential, in comparison with the monomer phloroglucinol. Trifucodiphlorethol A, trifucotriphlorethol A as well as fucotriphlorethol A were identified as strong radical scavengers, with IC(50) values for scavenging of 1,1-diphenyl-2 picrylhydrazyl radicals (DPPH) in the range of 10.0-14.4 microg/ml. All three compounds potently scavenged peroxyl radicals in the oxygen radical absorbance capacity (ORAC) assay. In addition, the compounds were shown to inhibit cytochrome P450 1A activity with IC(50) values in the range of 17.9-33 microg/ml, and aromatase (Cyp19) activity with IC(50) values in the range of 1.2-5.6 microg/ml.
Asunto(s)
Antioxidantes/farmacología , Inhibidores de la Aromatasa/farmacología , Compuestos de Bifenilo/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Fucus/química , Éteres Fenílicos/farmacología , Floroglucinol/farmacología , Compuestos de Terfenilo/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/aislamiento & purificación , Antioxidantes/uso terapéutico , Inhibidores de la Aromatasa/aislamiento & purificación , Inhibidores de la Aromatasa/uso terapéutico , Compuestos de Bifenilo/aislamiento & purificación , Compuestos de Bifenilo/uso terapéutico , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Ratones , Neoplasias/tratamiento farmacológico , Éteres Fenílicos/aislamiento & purificación , Éteres Fenílicos/uso terapéutico , Floroglucinol/análogos & derivados , Floroglucinol/uso terapéutico , Picratos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Compuestos de Terfenilo/aislamiento & purificación , Compuestos de Terfenilo/uso terapéuticoRESUMEN
A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs 17 and 21 were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs 16 and 20, respectively, albeit with some decrease in COX-2 selectivity. Structure-activity relationship studies have determined that incorporation of two fluorine atoms in the central phenyl group, as in 20 and 21, is extremely advantageous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several noticeable examples in the 1,2-diaryl-4,5-difluorobenzenesulfonamide series are 21a-c,k,l,n (COX-2, IC50 = 0.002-0.004 microM), in which all have in vitro COX-1/COX-2 selectivity > 1000. In addition, sulfonamides 21a,b,d,g,j,m,n,q were shown to have greatly enhanced oral activity with more than 90% inhibition of prostaglandin E2 production in the air pouch model of inflammation. Furthermore, sulfonamide 21b was found to be very active in the rat adjuvant-induced arthritis model (ED50 = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED50 = 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200 mg/kg.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Compuestos de Terfenilo/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/uso terapéutico , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratas , Compuestos de Terfenilo/administración & dosificación , Compuestos de Terfenilo/química , Compuestos de Terfenilo/uso terapéuticoAsunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Antagonistas de Estrógenos/uso terapéutico , Estrógenos/uso terapéutico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Línea Celular , Ciclofenil/análogos & derivados , Ciclofenil/uso terapéutico , ADN/análisis , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Receptores de Estrógenos/metabolismo , Relación Estructura-Actividad , Compuestos de Terfenilo/uso terapéuticoRESUMEN
Antitumor evaluation of 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyltriphenylphosphonium bromide (1) revealed significant activity in P-388 lymphocytic leukemia (T/C = 160%). As a follow-up to this chemical lead, a series of closely related phosphonium salts was prepared in which the 1,3-dihydro-1,3-dioxo-2H-isoindole ring system was maintained or in which it was replaced by other moieties such as maleimido, bromo, methoxy, and isoindoline. Syntheses generally involved treatment of the appropriate N-(bromoalkyl)phthalimide with the required phosphine or condensation of the K salt of the substituted imide with beta-(bromoethyl)triphenylphosphonium bromide (12). From the biological data obtained for these compounds, several requirements can be defined for substantial antileukemic activity. Of utmost importance is the presence of a triarylphosphonium halide moiety, coupled to an alkyl chain of two or three carbon atoms. The preferred terminus of the alkyl chain is the 1,3-dihydro-1,3-dioxo-2H-isoindole ring system, although the observed activity of beta-(bromoethyl)-triphenylphosphonium bromide (12) (T/C = 127%) would suggest that a superior carrier molecule could be developed.