RESUMEN
A wide variety of substituted quinolines are readily synthesized under mild reaction conditions by the 6-endo-dig electrophilic cyclization of N-(2-alkynyl)anilines by ICl, I(2), Br(2), PhSeBr and p-O(2)NC(6)H(4)SCl. The reaction affords 3-halogen-, selenium- and sulfur-containing quinolines in moderate to good yields in the presence of various functional groups. Analogous quinolines bearing a hydrogen in the 3-position have been synthesized by the Hg(OTf)(2)-catalyzed ring closure of these same alkynylanilines.
RESUMEN
OBJECTIVES: Disinfection of the tooth pulp-canal system is imperative to successful endodontic therapy. Yet, studies suggest that 30-50% of current endodontic treatments fail from residual bacterial infection. Photodynamic therapy using red-light chromophores (630 nm) to induce antimicrobial death mediated by generated reactive oxygen species (ROS) has been reported, but red-light also may thermally damage resident tissues. In the current study, we tested the hypothesis that several blue light chromophores (380-500 nm) generate intracellular reactive oxygen species but are not cytotoxic to mammalian cells. METHODS: THP1 monocytes were exposed to 10 microM of four chromophores (chlorin e6, pheophorbide-a, pheophorbide-a-PLL, and riboflavin) for 30 min before activation with blue light (27J/cm(2), 60s). After activation, intracellular ROS were measured using a dihydrofluorescein diacetate technique, and cytotoxicity was determined by measuring mitochondrial activity with the MTT method. RESULTS: All photosensitizers produced intracellular ROS levels that were dependent on both the presence of the photosensitizer and blue light exposure. Riboflavin and pheophorbide-a-PLL produced the highest levels of ROS. Photosensitizers except riboflavin exhibited cytotoxicity above 10 microM, and all except pheophorbide-a-PLL were more cytotoxic after blue light irradiation. SIGNIFICANCE: The current study demonstrated the possible utility of blue light chromophores as producers of ROS that would be useful for endodontic disinfection.
Asunto(s)
Monocitos/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Clorofila/administración & dosificación , Clorofila/análogos & derivados , Clorofila/farmacología , Clorofilidas , Colorantes , Fluoresceínas , Colorantes Fluorescentes , Humanos , Luz , Mitocondrias/efectos de los fármacos , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacología , Polilisina/administración & dosificación , Polilisina/farmacología , Porfirinas/administración & dosificación , Porfirinas/farmacología , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Riboflavina/administración & dosificación , Riboflavina/farmacología , Succinato Deshidrogenasa/efectos de los fármacos , Sales de Tetrazolio , TiazolesRESUMEN
A targeting strategy based on the selective enzyme-mediated activation of polymeric photosensitizer prodrugs (PPP) within pathological tissue has led to the development of agents with the dual ability to detect and treat cancer. Herein, a detailed study of a simple model system for these prodrugs is described. We prepared "first-generation" PPP by directly tethering the photosensitizer (PS) pheophorbide a to poly-(L)-lysine via epsilon amide links and observed that by increasing the number of PS on a polymer chain, energy transfer between PS units improved leading to better quenching efficiency. Fragmentation of the PPP backbone by trypsin digestion gave rise to a pronounced fluorescence increase and to more efficient generation of reactive oxygen species upon light irradiation. In vitro tests using the T-24 bladder carcinoma cell line and ex vivo experiments using mouse intestines illustrated the remarkable and selective ability of these PPP to fluoresce and induce phototoxicity upon enzymatic activation. This work elucidated the basic physicochemical parameters, such as water solubility and quenching/activation behavior, required for the future elaboration of more adaptable "second-generation" PPP, in which the PS is tethered to a proteolytically stable polymer backbone via enzyme-specific peptide linkers. This polymer architecture offers great flexibility to tailor make the PPP to target any pathological tissue known to over-express a specific enzyme.
Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Polímeros/farmacología , Profármacos/uso terapéutico , Animales , Ratones , Ratones Endogámicos C57BLRESUMEN
The introduction of lipophilic derivatives of the naturally occurring heme precursor 5-aminolevulinic acid (5-ALA) into photomedicine has led to a true revival of this research area. 5-ALA-mediated photodynamic therapy (PDT) and fluorescence photodetection (FD) of neoplastic disease is probably one of the most selective cancer treatments currently known in oncology. To date, this method has been assessed experimentally for the treatment of various medical indications. However, the limited local bioavailability of 5-ALA has widely prevented its use in daily clinical practice. Although researchers were already aware of this drawback early during the development of 5-ALA-mediated PDT, only recently have well-established concepts in pharmaceutical science been adapted to investigate ways to overcome this drawback. Recently, two derivatives of 5-ALA, methylaminolevulinate (MAL) and hexylaminolevulinate (HAL), gained marketing authorization from the regulatory offices in Europe and Australia. MAL is marketed under the trade name Metvix for the treatment of actinic keratosis and difficult-to-treat basal cell carcinoma. HAL has recently been launched under the trade name Hexvix to improve the detection of superficial bladder cancer in Europe. This review will first present the fundamental concepts underlying the use of 5-ALA derivatives in PDT and FD from a chemical, biochemical and pharmaceutical point of view. Experimental evidences from preclinical data on the improvements and limits observed with 5-ALA derivatives will then be introduced. The state-of-the-art from clinical studies with 5-ALA esters will be discussed, with special emphasis placed on the process that led to the development of MAL in dermatology and to HAL in urology. Finally, we will discuss promising medical fields in which use of 5-ALA derivatives might potentially lead to further use of this methodology in photomedicine.
Asunto(s)
Ácido Aminolevulínico/análogos & derivados , Ácido Aminolevulínico/uso terapéutico , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Animales , Humanos , Peso Molecular , Fotoquímica , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Early cancer diagnosis is of the most crucial factors determining proper patient management and long-term survival. Thus, there is considerable interest in developing more reliable methods for cancer diagnosis. Fluorescence diagnosis using metabolic alterations of neoplasia has emerged as a powerful new biomedical tool. It is characterized by superior sensitivity and selectivity over other methods, and it offers the possibility to obtain molecular information required to determine the state of the disease. Furthermore, important advancements have been made in generating deeper three-dimensional images in vivo by exploiting tissue transparency in the near-infrared region and fluorescence-mediated tomography, which might render fluorescence diagnosis less invasive. From basic principles in optics and molecular biology to the development of medical instrumentation and the launching of clinical trials, we have comprehensively compiled the basic information required to clearly understand fundamental aspects of fluorescence-based diagnosis.
Asunto(s)
Neoplasias/diagnóstico , Ácido Aminolevulínico , Animales , Diagnóstico por Imagen/métodos , Sistemas de Liberación de Medicamentos , Fluorescencia , Glucólisis , Hemo/biosíntesis , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Péptido Hidrolasas/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes , Porfirinas/uso terapéuticoRESUMEN
The monitoring of diabetes mellitus, as it develops and becomes clinically evident, remains a major challenge for diagnostic imaging in clinical practice. Here we present a novel approach to beta-cell imaging by targeting the sulphonylurea receptor subtype 1 (SUR1), using multivalent derivatives of the anti-diabetic drug glibenclamide. Since glibenclamide has a high affinity for SUR1 but does not contain a suitable functional group to be linked to an imaging probe, we have synthesized 11 glibenclamide derivatives and evaluated their affinity to SUR1 in MIN6 cells. The most promising compound has been used to obtain multivalent glibenclamide-polyamidoamine (PAMAM) derivatives, containing up to 15 sulphonylurea moieties per dendrimer. The remaining functional groups on the dendrimers can consecutively be used for labeling with reporter groups for different imaging modalities, thus allowing for multifunctional imaging, and for the modification of pharmacokinetic properties. We synthesized fluorochrome-labeled multivalent probes, that demonstrate in cellular assays affinities to SUR1 in the nanomolar range, superior to native glibenclamide. The probes specifically label MIN6 cells, but not HeLa or PANC-1 cells which do not express SUR1. A very low cytotoxicity of the multivalent probes is demonstrated by the persistent release of insulin from MIN6 cells exposed to high glucose concentrations. Furthermore, the probes display positive labeling of beta-cells of primary mouse and human islet-cells ex vivo and of islets of Langerhans in vivo. The data document that multivalent probes based on glibenclamide derivatives provide a suitable platform for further developments of cell-specific probes, and can be adapted for multiple imaging modalities, including those that are now used in the clinics.
Asunto(s)
Diagnóstico por Imagen , Gliburida/farmacología , Islotes Pancreáticos/metabolismo , Sondas Moleculares/química , Animales , Muerte Celular/efectos de los fármacos , Dendrímeros/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Gliburida/síntesis química , Gliburida/química , Células HeLa , Humanos , Islotes Pancreáticos/efectos de los fármacos , Ligandos , Ratones , Microscopía Confocal , Especificidad de Órganos/efectos de los fármacos , Receptores de Sulfonilureas/metabolismoRESUMEN
Quinolines substituted in the 3-position by an iodo or phenylseleno group are readily prepared in good to excellent yields by the reaction of propargylic anilines with appropriate electrophiles under mild reaction conditions. [reaction: see text]
Asunto(s)
Alquinos/química , Compuestos de Anilina/química , Quinolinas/síntesis química , Catálisis , Ciclización , Estructura Molecular , Quinolinas/análisisRESUMEN
The reaction of 2-(arylethynyl)biphenyls with ICl at -78 degrees C affords substituted polycyclic aromatic iodides in good to excellent yields. The aryl substituents can be either electron-donating or electron-withdrawing groups such as OMe, Me, CHO, CO(2)Et or NO(2) groups. This chemistry has been successfully extended to systems containing a variety of polycyclic and heterocyclic rings. [reaction: see text]
RESUMEN
We have developed novel polymeric photosensitizer prodrugs (PPPs) for improved photodynamic therapy. In PPPs, multiple photosensitizer units are covalently coupled to a polymeric backbone via protease-cleavable peptide linkers. These initially non-photoactive compounds become fluorescent and phototoxic after specific enzymatic cleavage of the peptide linkers and subsequent release of the photosensitizer moieties. Tethering the photosensitizer via a short and easily modified amino acid sequence to the polymeric backbone allows for the targeting of a wide variety of proteases. Model compounds, sensitive to trypsin-mediated cleavage, with different pheophorbide a-peptide loading ratios and backbone net charges were evaluated with respect to their solubility, "self-quenching" capacity of fluorescence emission, and reactive oxygen species (ROS) generation. In addition, linker sequence impaired selectivity toward enzymatic cleavage was demonstrated either by incubating PPPs with different enzymes having trypsin-like activity or by introducing a single d-arginine mutant in the peptide sequence. In vitro cell culture tests confirmed dose-dependent higher phototoxicity of enzymatically activated PPPs compared to the nonactivated conjugate after irradiation with white light. These data suggest that similar compounds adapted to disease-associated proteases can be used for selective photodynamic therapy.
Asunto(s)
Clorofila/análogos & derivados , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Profármacos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clorofila/química , Clorofila/farmacología , Humanos , Péptidos/química , Fármacos Fotosensibilizantes/farmacología , Polilisina/química , Profármacos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Tripsina/químicaRESUMEN
Biologically interesting fluoren-9-one and xanthen-9-one derivatives have been prepared by a novel aryl to imidoyl palladium migration, followed by intramolecular arylation. The fluoren-9-one synthesis appears to involve both a palladium migration mechanism and a C-H activation process proceeding through an unprecedented organopalladium(IV) hydride intermediate. The results from deuterium labeling experiments are consistent with the proposed dual mechanism.
Asunto(s)
Fluorenos/síntesis química , Paladio/química , Xantonas/síntesis química , Deuterio/química , Fluorenos/química , Xantonas/químicaRESUMEN
A novel 1,4-palladium migration between the o- and o'-positions of biaryls has been observed in organopalladium intermediates derived from o-halobiaryls. The organopalladium intermediates generated by this migration have been trapped either by a Heck reaction employing ethyl acrylate or by Suzuki cross-coupling using arylboronic acids. This palladium migration can be activated or deactivated by choosing the appropriate reaction conditions. Chemical and computational evidence supports the presence of an equilibrium that correlates with the C-H acidity of the available arene positions.
RESUMEN
[reaction: see text] A variety of substituted polycyclic aromatics are readily prepared in good to excellent yields under very mild reaction conditions by the reaction of 2-(1-alkynyl)biphenyls with ICl, I(2), NBS, and p-O(2)NC(6)H(4)SCl. This methodology readily accommodates various functional groups and has been successfully extended to systems containing a variety of polycyclic and heterocyclic rings.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Paladio/química , Hidrocarburos Policíclicos Aromáticos/síntesis química , Catálisis , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/análisis , Indicadores y Reactivos , Estructura Molecular , Hidrocarburos Policíclicos Aromáticos/análisisRESUMEN
A novel 1,4-palladium migration in organopalladium intermediates derived from o-iodobiaryls has been observed under modified Heck reaction conditions. This migration process can be switched "on" or "off" by simply choosing the appropriate reaction conditions.
RESUMEN
The synthesis of various substituted fluoren-9-ones has been accomplished by the palladium-catalyzed cyclocarbonylation of o-halobiaryls. The cyclocarbonylation of 4'-substituted 2-iodobiphenyls produces very high yields of 2-substituted fluoren-9-ones bearing either electron-donating or electron-withdrawing substituents. 3'-Substituted 2-iodobiphenyls afford 3-substituted fluoren-9-ones in excellent yields with good regioselectivity. This chemistry has been successfully extended to polycyclic fluorenones and fluorenones containing fused isoquinoline, indole, pyrrole, thiophene, benzothiophene, and benzofuran rings.
RESUMEN
Novel palladium migration/arylation methodology for the synthesis of complex fused polycycles has been developed, in which one or more sequential Pd-catalyzed intramolecular migration processes involving C-H activation are employed. The chemistry works best with electron-rich aromatics, which is in agreement with the idea that these palladium-catalyzed C-H activation reactions parallel electrophilic aromatic substitution.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Paladio/química , Compuestos Policíclicos/síntesis química , Catálisis , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Policíclicos/químicaRESUMEN
A novel palladium migration methodology for the synthesis of complex fused polycycles has been developed. This process involves 1,4-palladium alkyl to aryl migrations via through-space C-H activation, followed by intramolecular arylation or an intermolecular Heck reaction providing a very efficient way to synthesize fused ring systems.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Paladio/química , Compuestos Policíclicos/síntesis química , Catálisis , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , Compuestos Policíclicos/químicaRESUMEN
A novel palladium migration/arylation methodology for the synthesis of complex fused polycycles has been developed, in which one or more sequential Pd-catalyzed intramolecular migration processes involving C-H activation are employed. The chemistry works best with electron-rich aromatics, which is in agreement with the idea that these palladium-catalyzed C-H activation reactions parallel electrophilic aromatic substitution.