RESUMEN
The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as "unconventional" therapeutics with precise spatiotemporal control by using light stimuli may open entirely new horizons for innovative therapeutic modalities. Among ROS and RNS, peroxynitrite (ONOO-) plays a dominant role in chemistry and biology in view of its potent oxidizing power and cytotoxic action. We have designed and synthesized a molecular hybrid based on benzophenothiazine as a red light-harvesting antenna joined to an N-nitroso appendage through a flexible spacer. Single photon red light excitation of this molecular construct triggers the release of nitric oxide (ËNO) and simultaneously produces superoxide anions (O2Ë-). The diffusion-controlled reaction between these two radical species generates ONOO-, as confirmed by the use of fluorescein-boronate as a highly selective chemical probe. Besides, the red fluorescence of the hybrid allows its tracking in different types of cancer cells where it is well-tolerated in the dark but induces remarkable cell mortality under irradiation with red light in a very low concentration range, with very low light doses (ca. 1 J cm-2). This ONOO- generator activatable by highly biocompatible and tissue penetrating single photon red light can open up intriguing prospects in biomedical research, where precise and spatiotemporally controlled concentrations of ONOO- are required.
RESUMEN
We herein report a study on a set of hybrid compounds in which 3-R-substituted furoxan moieties (R = CH3, CONH2, CN, SO2C6H5), endowed with varying NO-releasing capacities, are joined to a mitochondrial probe, rhodamine B. Each product has been investigated for its ability to release NO both in physiological solution, in the presence of cysteine, and in A549 lung adenocarcinoma cancer cells. The cytotoxicity of all the products against the aforementioned cancer cells has been assessed, including the structurally related compounds with no mitochondrial targeting, which were taken as a reference. In the case of the models bearing the -CH3 and -CONH2 groups at the 3-position on the furoxan, only the targeted models showed a significant cytotoxic activity, and only at the highest concentrations, in accordance with their weak NO-releasing properties. On the contrary, the presence of the strong electron-withdrawing groups, as -CN and -SO2C6H5, at the 3-position gave rise to anticancer agents, likely because of the high NO-releasing and of their capability of inhibiting cellular proteins by covalent binding. In detail, the rhodamine hybrid containing the 3-SO2C6H5 substituted furoxan moiety emerged as the most interesting product as it showed high cytotoxicity over the entire concentration range tested. This substructure was also linked to a phenothiazine scaffold that is able to accumulate in lysosomes. Nevertheless, mitochondrial targeting for these NO-donor furoxan substructures was found to be the most efficient.
Asunto(s)
Antineoplásicos/farmacología , Óxido Nítrico/metabolismo , Orgánulos/química , Oxadiazoles/farmacología , Células A549 , Antineoplásicos/química , Antineoplásicos/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Orgánulos/metabolismo , Oxadiazoles/química , Oxadiazoles/metabolismo , Relación Estructura-ActividadRESUMEN
We report for the first time a NO photodonor (NOPD) operating with the widely used chemotherapeutic agent doxorubicin (DOX) as the light-harvesting antenna. This permits NO uncaging from an N-nitroso appendage upon selective excitation of DOX with highly biocompatible green light, without precluding its typical red emission. This NOPD effectively binds DNA and photodelivers NO nearby, representing an intriguing candidate for potential multimodal therapeutic applications based on the combination of DOX and NO.
Asunto(s)
Antineoplásicos/química , Materiales Biocompatibles/química , Doxorrubicina/química , Luz , Óxido Nítrico/química , Humanos , Estructura MolecularRESUMEN
A novel molecular hybrid has been designed and synthesized in which acridine orange (AO) is covalently linked to an N-nitrosoaniline derivative through an alkyl spacer. Photoexcitation of the AO antenna with the highly biocompatible green light results in intense fluorescence emission and triggers NO detachment from the N-nitroso appendage via an intramolecular electron transfer. The presence of the AO moiety encourages the binding with DNA through both external and partially intercalative fashions, depending on the DNA:molecular hybrid molar ratio. Importantly, this dual-mode binding interaction with the biopolymer does not preclude the NO photoreleasing performances of the molecular hybrid, permitting NO to be photogenerated nearby DNA with an efficiency similar to that of the free molecule. These properties make the presented compound an intriguing candidate for fundamental and potential applicative research studies where NO delivery in the DNA proximity precisely regulated by harmless green light is required.
Asunto(s)
Naranja de Acridina , ADN , Óxido Nítrico , Colorantes Fluorescentes , Luz , Nitrosaminas , Procesos Fotoquímicos , Espectrometría de FluorescenciaRESUMEN
The engineering of photosensitizers (PS) for photodynamic therapy (PDT) with nitric oxide (NO) photodonors (NOPD) is broadening the horizons for new and yet to be fully explored unconventional anticancer treatment modalities that are entirely controlled by light stimuli. In this work, we report a tailored boron-dipyrromethene (BODIPY) derivative that acts as a PS and a NOPD simultaneously upon single photon excitation with highly biocompatible green light. The photogeneration of the two key species for PDT and NOPDT, singlet oxygen (1O2) and NO, has been demonstrated by their direct detection, while the formation of NO is shown not to be dependent on the presence of oxygen. Biological studies carried out using A375 and SKMEL28 cancer cell lines, with the aid of suitable model compounds that are based on the same BODIPY light harvesting core, unambiguously reveal the combined action of 1O2 and NO in inducing amplified cancer cell mortality exclusively under irradiation with visible green light.
RESUMEN
Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Resistencia a Antineoplásicos , Ácido Hialurónico/administración & dosificación , Sulfuro de Hidrógeno/administración & dosificación , Osteosarcoma/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/metabolismo , Composición de Medicamentos , Liberación de Fármacos , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/química , Ácido Hialurónico/metabolismo , Sulfuro de Hidrógeno/química , Sulfuro de Hidrógeno/metabolismo , Liposomas , Ratones Endogámicos BALB C , Osteosarcoma/genética , Osteosarcoma/metabolismo , Osteosarcoma/patología , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Two novel NO photodonors (NOPDs) based on BODIPY and Rhodamine antennae activatable with the highly biocompatible green light are reported. Both NOPDs exhibit considerable fluorescence emission and release NO with remarkable quantum efficiencies. The combination of the photoreleasing and emissive performance for both compounds is superior to those exhibited by other NOPDs based on similar light-harvesting centres, making them very intriguing for image-guided phototherapeutic applications. Preliminary biological data prove their easy visualization in cell environment due to the intense green and orange-red fluorescence and their photodynamic action on cancer cells due to the NO photo-liberated.
RESUMEN
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00016.].
RESUMEN
Combination of photosensitizers (PS) for photodynamic therapy with NO photodonors (NOPD) is opening intriguing horizons towards new and still underexplored multimodal anticancer and antibacterial treatments not based on "conventional" drugs and entirely controlled by light stimuli. In this contribution, we report an intriguing molecular hybrid based on a BODIPY light-harvesting antenna that acts simultaneously as PS and NOPD upon single photon excitation with the highly biocompatible green light. The presented hybrid offers a combination of superior advantages with respect to the other rare cases reported to date, meeting most of the key criteria for both PSs and NOPDs in the same molecular entity such as: (i) capability to generate 1O2 and NO with single photon excitation of biocompatible visible light, (ii) excellent 1O2 quantum yield and NO quantum efficiency, (iii) photogeneration of NO independent from the presence of oxygen, (iv) large light harvesting properties in the green region. Furthermore, this compound together with its stable photoproduct, is well tolerated by both normal and cancer cells in the dark and exhibits bimodal photomortality of cancer cells under green light excitation due to the combined action of the cytotoxic 1O2 and NO.
Asunto(s)
Compuestos de Boro/farmacología , Donantes de Óxido Nítrico/farmacología , Nitrosaminas/farmacología , Fármacos Fotosensibilizantes/farmacología , Antineoplásicos/farmacología , Antineoplásicos/efectos de la radiación , Antineoplásicos/toxicidad , Compuestos de Boro/efectos de la radiación , Compuestos de Boro/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Luz , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/efectos de la radiación , Donantes de Óxido Nítrico/toxicidad , Nitrosaminas/efectos de la radiación , Nitrosaminas/toxicidad , Fármacos Fotosensibilizantes/efectos de la radiación , Fármacos Fotosensibilizantes/toxicidad , Oxígeno Singlete/metabolismoRESUMEN
Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of H2S-releasing doxorubicins (Sdox) that were more effective than doxorubicin against resistant osteosarcoma cells. Here we investigated the molecular mechanisms of the higher efficacy of Sdox in human osteosarcoma cells with increasing resistance to doxorubicin. Differently from doxorubicin, Sdox preferentially accumulated within the endoplasmic reticulum (ER), and its accumulation was only modestly reduced in Pgp-expressing osteosarcoma cells. The increase in doxorubicin resistance was paralleled by the progressive down-regulation of genes of ER-associated protein degradation/ER-quality control (ERAD/ERQC), two processes that remove misfolded proteins and protect cell from ER stress-triggered apoptosis. Sdox, that sulfhydrated ER-associated proteins and promoted their subsequent ubiquitination, up-regulated ERAD/ERQC genes. This up-regulation, however, was insufficient to protect cells, since Sdox activated ER stress-dependent apoptotic pathways, e.g., the C/EBP-ß LIP/CHOP/PUMA/caspases 12-7-3 axis. Sdox also promoted the sulfhydration of Pgp that was subsequently ubiquitinated: this process further enhanced Sdox retention and toxicity in resistant cells. Our work suggests that Sdox overcomes doxorubicin resistance in osteosarcoma cells by at least two mechanisms: it induces the degradation of Pgp following its sulfhydration and produces a huge misfolding of ER-associated proteins, triggering ER-dependent apoptosis. Sdox may represent the prototype of innovative anthracyclines, effective against doxorubicin-resistant/Pgp-expressing osteosarcoma cells by perturbing the ER functions.
Asunto(s)
Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Antibióticos Antineoplásicos/uso terapéutico , Apoptosis , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Humanos , Immunoblotting , Concentración 50 Inhibidora , Reacción en Cadena de la PolimerasaRESUMEN
A few compounds in which the nitric oxide (NO) photodonor N-[4-nitro-3-(trifluoromethyl)phenyl]propane-1,3-diamine is joined to the mitochondria-targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by measuring their partition coefficients in n-octanol/water. The obtained values, markedly lower than those calculated, are consistent with the likely collapsed conformation assumed by the compounds in solution, as suggested by molecular dynamics simulations. The capacity of the compounds to release NO under visible light irradiation was evaluated by measuring nitrite production by means of the Griess reaction. The accumulation of compounds in the mitochondria of human lung adenocarcinoma A549 cells was assessed by UPLC-MS. Interestingly, compound 13 [(9-((3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)amino)-9-oxononyl) triphenylphosphonium bromide] displayed both the highest accumulation value and high toxicity toward A549 cells upon irradiation-mediated NO release in mitochondria.
Asunto(s)
Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Mitocondrias/metabolismo , Donantes de Óxido Nítrico/farmacología , Compuestos Organofosforados/farmacología , Células A549 , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/efectos de la radiación , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Luz , Conformación Molecular , Simulación de Dinámica Molecular , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/efectos de la radiación , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/química , Compuestos Organofosforados/efectos de la radiaciónRESUMEN
The design, synthesis, spectroscopic and photochemical properties, and biological evaluation of a novel molecular hybrid that is able to deliver nitric oxide (NO) into mitochondria are reported. This molecular conjugate unites a tailored o-CF3 -p-nitroaniline chromophore, for photo-regulated NO release, and a rhodamine moiety, for mitochondria targeting, in the same molecular skeleton via an alkyl spacer. A combination of steady-state and time-resolved spectroscopic and photochemical experiments demonstrate that the two chromogenic units preserve their individual photophysical and photochemical properties in the conjugate quite well. Irradiation with violet light triggers NO release from the nitroaniline moiety and photoionization in the rhodamine center, which also retains considerable fluorescence efficiency. The molecular hybrid preferentially accumulates in the mitochondria of A549 lung adenocarcinoma cells where it induces toxicity at a concentration of 1â µm, exclusively upon irradiation. Comparative experiments, carried out with ad-hoc-synthesized model compounds, suggest that the phototoxicity observed at such a low concentration is probably not due to NO itself, but rather to the formation of the highly reactive peroxynitrite that is generated from the reaction of NO with the superoxide anion.
Asunto(s)
Mitocondrias/metabolismo , Óxido Nítrico/metabolismo , Fármacos Fotosensibilizantes/química , Rayos Ultravioleta , Células A549 , Compuestos de Anilina/química , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Microscopía Fluorescente , Mitocondrias/efectos de los fármacos , Óxido Nítrico/química , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacología , Rodaminas/químicaRESUMEN
Drug efflux transporters, in particular P-glycoprotein (Pgp), limit the success of chemotherapy. We previously found that synthetic doxorubicin conjugated with nitric oxide (NO)-releasing group overcomes resistance by inducing a NO-mediated inhibition of Pgp. Here we produced the first liposomal formulations of this nitrooxy-doxorubicin decorated with folic acid (FA), termed LNDF, in order to improve their active targeting against Pgp-expressing tumors. Folate was inserted onto liposomes surface using two different methods and the formulations were compared with respect to their technological features and in vitro behavior. By analyzing human and murine breast cancer cells with different expression of FA receptor (FAR) and Pgp, we demonstrated that LNDF are internalized in a FAR-dependent manner and achieve maximal anti-tumor efficacy against FAR-positive/Pgp-positive cells. Upon uptake of LNDF, nitrooxy-doxorubicin was delivered within nucleus, where it induced cell cycle arrest and DNA damages, and mitochondria, where it impaired the mitochondrial energy metabolism and triggered mitochondria-dependent apoptosis. LNDF reduced the growth of FAR-positive/Pgp-positive tumors and prevented tumor formation in mice, whereas doxorubicin and Caelyx® failed. LNDF cardiotoxicity was comparable to Caelyx®. The sensitivity to LNDF was maintained in tumors exposed to repeated cycles of the drug and in cells derived from the exposed tumors, excluding the onset of secondary resistance. By combining an innovative multitarget cargo drug, conceived to achieve high efficacy against Pgp-expressing cells, and appropriate strategies of liposome formulation and decoration, we produced a therapeutic tool that may represent a significant advancement in the treatment of FAR-positive/Pgp-positive tumors.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Ácido Fólico/administración & dosificación , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Óxido Nítrico/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Doxorrubicina/química , Femenino , Ácido Fólico/química , Transportadores de Ácido Fólico/metabolismo , Humanos , Liposomas , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Óxido Nítrico/química , RatasRESUMEN
Using a facile synthetic route, an organic NO release agent based on a BODIPY light-harvesting antenna was devised. This compound is stable in the dark and delivers NO under photoexcitation with biologically favorable green light. Temporally regulated vasodilation capability is demonstrated on rat aorta by green-light-induced NO release.
Asunto(s)
Donantes de Óxido Nítrico/química , Óxido Nítrico/química , Compuestos de Boro/química , Cromatografía Líquida de Alta Presión/métodos , Liberación de Fármacos , Humanos , Luz , Fotones , Espectrometría de Fluorescencia/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Vasodilatación/efectos de los fármacosRESUMEN
Nitric oxide (NO) release from a suitable NO photodonor (NOP) can be fine-tuned by visible light stimuli at doses that are not toxic to cells but that inhibit several efflux pumps; these are mainly responsible for the multidrug resistance of the anticancer agent doxorubicin (DOX). The strategy may thus increase DOX toxicity against resistant cancer cells. Moreover, a novel molecular hybrid covalently joining DOX and NOP showed similar increased toxicity toward resistant cancer cells and, in addition, lower cardiotoxicity than DOX. This opens new and underexplored approaches to overcoming the main therapeutic drawbacks of this chemotherapeutic based on light-controlled release of NO.
RESUMEN
A small series of water-soluble NO-donor furoxans bearing a basic center at the 4-position, having a wide lipophilic-hydrophilic balance range, and endowed with different NO-release capacities, were synthesized and characterized. Selected members were studied for their IOP-lowering activity in the transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compounds 3 and 7, whose activity 60min after administration was similar to that of Timolol. Notably, 7 was characterized by a long-lasting action. The IOP-lowering activity in this series of products appeared to be modulated by the lipophilic-hydrophilic balance rather than by the NO-donor capacity.
Asunto(s)
Oxadiazoles/química , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Modelos Animales de Enfermedad , Glaucoma/tratamiento farmacológico , Presión Intraocular/efectos de los fármacos , Óxido Nítrico/metabolismo , Hipertensión Ocular/tratamiento farmacológico , Hipertensión Ocular/patología , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Conejos , Solubilidad , Timolol/farmacología , Timolol/uso terapéuticoRESUMEN
P-glycoprotein (P-gp) is a well-known membrane transporter expressed in a number of strategic biological barriers, where it exerts a protective effect of paramount importance. Conversely it is one of the main causes of multidrug resistance (MDR), being capable of effluxing many chemotherapeutics. In a development of previous research, a small library of compounds was created conjugating diversely substituted furazan rings with MC70, a well-known P-gp inhibitor. These compounds were assessed for their potency against P-gp and another transporter (MRP1), for their apparent permeability (Papp) and for their ability to induce ATPase activity, thus delineating a complete functional profile. They displayed a substrate mechanism of action and high selectivity toward P-gp, unlike the lead compound. Data relating to their activity range from low micromolar to sub-nanomolar EC50, the most interesting compounds being 15 (0.97 nM), 19 (1.3 nM), 25 (0.60 nM), and 27 (0.90 nM).
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Compuestos de Bifenilo/farmacología , Tetrahidroisoquinolinas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/químicaRESUMEN
Doxorubicin (DOXO) is one of the most effective antineoplastic agents in clinical practice. Its use is limited by acute and chronic side effects, in particular by its cardiotoxicity and by the rapid development of resistance to it. As part of a program aimed at developing new DOXO derivatives endowed with reduced cardiotoxicity, and active against DOXO-resistant tumor cells, a series of H2S-releasing DOXOs (H2S-DOXOs) were obtained by combining DOXO with appropriate H2S donor substructures. The resulting compounds were studied on H9c2 cardiomyocytes and in DOXO-sensitive U-2OS osteosarcoma cells, as well as in related cell variants with increasing degrees of DOXO-resistance. Differently from DOXO, most of the products were not toxic at 5 µM concentration on H9c2 cells. A few of them triggered high activity on the cancer cells. H2S-DOXOs 10 and 11 emerged as the most interesting members of the series. The capacity of 10 to impair Pgp transporter is also discussed.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sulfuro de Hidrógeno/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Antineoplásicos/efectos adversos , Antineoplásicos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Sulfuro de Hidrógeno/farmacología , Estructura Molecular , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
The design, synthesis, photochemical properties, and biological evaluation of a novel photoactivatable bichromophoric conjugate are reported. The compound 1, [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)butanamide] combines a 2,6-diiodo-1,3,5,7-tetramethyl BODIPY derivative as singlet oxygen ((1) O2 ) photosensitizer and 4-nitro-3-(trifluoromethyl)aniline (NOPD) as nitric oxide (NO) photodonor, joined by an alkyl spacer. These two chromogenic units absorb in distinct regions of the visible spectrum, and their individual photochemical properties are conserved in the molecular conjugate. Irradiation of the bichromophoric conjugate with green light afforded (1) O2 in high quantum yields, whereas (1) O2 production was negligible with the use of blue light; under this latter condition, NO was released. Photogeneration of NO and cytotoxic (1) O2 can therefore be regulated by appropriately tuning the excitation light wavelength and intensity. Tested on melanoma cancer cells, this resulted in amplified photomortality relative to that of a structurally correlated model compound 2 [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-(p-tolylamino)propyl)butanamide] deprived of the NO-release capacity. The cellular uptake of 1, evaluated by confocal fluorescence microscopy, showed that the product is localized in the cytoplasm.
Asunto(s)
Muerte Celular/efectos de los fármacos , Luz , Neoplasias/patología , Óxido Nítrico/química , Oxígeno Singlete , Línea Celular Tumoral , Humanos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Hybrid products in which the dihydroartemisinin scaffold is combined with NO-donor furoxan and NONOate moieties have been synthesized and studied as potential tools for the treatment of cerebral malaria (CM). The designed products were able to dilate rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism. All hybrid compounds showed preserved antiplasmodial activity in vitro and in vivo against Plasmodium berghei ANKA, comparable to artesunate and artemether. Hybrid 10, selected for additional studies, was capable of increasing survival of mice with late-stage CM from 27.5% to 51.6% compared with artemether. Artemisinin-NO-donor hybrid compounds show promise as potential new drugs for treating cerebral malaria.