RESUMEN
Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 µM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 µM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.
Asunto(s)
Acetilcolinesterasa , Inhibidores de la Colinesterasa , Indazoles , Simulación del Acoplamiento Molecular , Tiazoles , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Simulación del Acoplamiento Molecular/métodos , Indazoles/farmacología , Indazoles/química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/efectos de los fármacos , Humanos , Tiazoles/farmacología , Tiazoles/química , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
Diazo compounds are organic substances that are often used as precursors in organic synthesis like cyclization reactions, olefinations, cyclopropanations, cyclopropenations, rearrangements, and carbene or metallocarbene insertions into C-H, N-H, O-H, S-H, and Si-H bonds. Typically, reactions from diazo compounds are catalyzed by transition metals with various ligands that modulate the capacity and selectivity of the catalyst. These ligands can modify and enhance chemoselectivity in the substrate, regioselectivity and enantioselectivity by reflecting these preferences in the products. Porphyrins have been used as catalysts in several important reactions for organic synthesis and also in several medicinal applications. In the chemistry of diazo compounds, porphyrins are very efficient as catalysts when complexed with low-cost metals (e.g., Fe and Co) and, therefore, in recent years, this has been the subject of significant research. This review will summarize the advances in the studies involving the field of diazo compounds catalyzed by metalloporphyrins (M-Porph, M = Fe, Ru, Os, Co, Rh, Ir) in the last five years to provide a clear overview and possible opportunities for future applications. Also, at the end of this review, the properties of artificial metalloenzymes and hemoproteins as biocatalysts for a broad range of applications, namely those concerning carbene-transfer reactions, will be considered.
RESUMEN
Since the occurrence of tumours is closely associated with the telomerase function and oncogene expression, the structure of such enzymes and genes are being recognized as targets for new anticancer drugs. The efficacy of several ligands in telomerase inhibition and in the regulation of genes expression, by an effective stabilisation of G-quadruplexes (G4) DNA structures, is being considered as a promising strategy in cancer therapies. When evaluating the potential of a ligand for telomerase inhibition, the selectivity towards quadruplex versus duplex DNA is a fundamental attribute due to the large amount of double-stranded DNA in the cellular nucleus. This study reports the evaluated efficacy of three tetracationic opp-dibenzoporphyrins, a free base, and the corresponding zinc(II) and nickel(II) complexes, to stabilise G4 structures, namely the telomeric DNA sequence (AG3(T2AG3)3). In order to evaluate the selectivity of these ligands towards G4 structures, their interaction towards DNA calf thymus, as a double-strand DNA sequence, were also studied. The data obtained by using different spectroscopic techniques, such as ultraviolet-visible, fluorescence, and circular dichroism, suggested good affinity of the free-base porphyrin and of its zinc(II) complex for the considered DNA structures, both showing a pattern of selectivity for the telomeric G4 structure. A pattern of aggregation in aqueous solution was detected for both Zn(II) and Ni(II) metallo dibenzoporphyrins and the ability of DNA sequences to induce ligand disaggregation was observed.
Asunto(s)
G-Cuádruplex , Telomerasa , Ligandos , ADN , Telómero/genéticaRESUMEN
Skin cancer is one of the cancers that registers the highest number of new cases annually. Among all forms of skin cancer, melanoma is the most invasive and deadliest. The resistance of this form of cancer to conventional treatments has led to the employment of alternative/complementary therapeutic approaches. Photodynamic therapy (PDT) appears to be a promising alternative to overcome the resistance of melanoma to conventional therapies. PDT is a non-invasive therapeutic procedure in which highly reactive oxygen species (ROS) are generated upon excitation of a photosensitizer (PS) when subjected to visible light of an adequate wavelength, resulting in the death of cancer cells. In this work, inspired by the efficacy of tetrapyrrolic macrocycles to act as PS against tumor cells, we report the photophysical characterization and biological assays of isobacteriochlorins and their corresponding chlorins and porphyrins against melanoma cancer cells through a photodynamic process. The non-tumoral L929 fibroblast murine cell line was used as the control. The results show that the choice of adequate tetrapyrrolic macrocycle-based PS can be modulated to improve the performance of PDT.
Asunto(s)
Dermatitis Fototóxica , Melanoma , Fotoquimioterapia , Porfirinas , Neoplasias Cutáneas , Humanos , Animales , Ratones , Fotoquimioterapia/métodos , Porfirinas/farmacología , Porfirinas/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Dermatitis Fototóxica/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Details on the unexpected formation of two new (dimethylamino)methyl corrole isomers from the reaction of 5,10,15-tris(pentafluorophenyl)corrolatogallium(III) with sarcosine and paraformaldehyde are presented. Semi-empirical calculations on possible mechanism pathways seem to indicate that the new compounds are probably formed through a Mannich-type reaction. The extension of the protocol to the free-base 5,10,15-tris(pentafluorophenyl)corrole afforded an unexpected new seven-membered ring corrole derivative, confirming the peculiar behavior of corroles towards known reactions when compared to the well-behaved porphyrin counterparts.
Asunto(s)
Porfirinas , Sarcosina , Porfirinas/química , IsomerismoRESUMEN
In this study, we report the preparation of new mono-charged benzoporphyrin complexes by reaction of the appropriate neutral benzoporphyrin with (2,2'-bipyridine)dichloroplatinum(II) and of the analogs' derivatives synthesized through alkylation of the neutral scaffold with iodomethane. All derivatives were incorporated into polyvinylpyrrolidone (PVP) micelles. The ability of the resultant formulations to generate reactive oxygen species was evaluated, mainly the singlet oxygen formation. Then, the capability of the PVP formulations to act as photosensitizers against bladder cancer cells was assessed. Some of the studied formulations were the most active photosensitizers causing a decrease in HT-1376 cells' viability. This creates an avenue to further studies related to bladder cancer cells.
Asunto(s)
Antineoplásicos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfirinas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Cationes/síntesis química , Cationes/química , Cationes/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfirinas/síntesis química , Porfirinas/química , Relación Estructura-Actividad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Anionic species are one of the most common pollutants in residual and freshwaters. The presence of anthropogenic anions in water drastically increases the toxicity to living beings. Here, we report the preparation of a new optical active material based on tri(tosylamino)phthalocyanines grafted to ferromagnetic silica nanoparticles for anion detection and removal. The new unsymmetrical phthalocyanines (Pcs) proved to be excellent chemosensors for several anions (AcO-, Br-, Cl-, CN-, F-, H2PO4-, HSO4-, NO2-, NO3-, and OH-) in dimethyl sulfoxide (DMSO). Furthermore, the Pcs were grafted onto magnetic nanoparticles. The resulting novel hybrid material showed selectivity and sensitivity towards CN-, F-, and OH- anions in DMSO with limit of detection (LoD) of ≈4.0 µM. In water, the new hybrid chemosensor demonstrated selectivity and sensitivity for CN- and OH- anions with LoD of ≈0.2 µM. The new hybrids are easily recovered using a magnet, allowing recyclability and reusability, after acidic treatment, without losing the sensing proprieties.
RESUMEN
Melanoma is the most dangerous form of skin cancer, with an abrupt growth of its incidence over the last years. It is extremely resistant to traditional treatments such as chemotherapy and radiotherapy, but therapies for this cancer are gaining attention. Photodynamic therapy (PDT) is considered an effective modality to treat several types of skin cancers and can offer the possibility to treat one of the most aggressive ones: melanoma. In this work, the effect of PDT on a melanotic cell line (B16F10 cells) was assessed by exposing cultured cells to 5,10,15-tris(pentafluorophenyl)-20-(4-pyridyl)porphyrin (PS1) and to its chlorin (PS2) and isobacteriochlorin (PS3) corresponding derivatives and red LED light (λ = 660 ± 20 nm). The PDT effect in the cells' viability was measured using the MTT assay. The cell apoptosis was quantified by flow cytometry, and the subcellular localization of the photosensitizer was determined by fluorescence microscopy. In addition, the ability of PS2 to generate superoxide radicals was qualitatively assessed by tyrosine nitration. The results show that the efficiency of the PDT process is dependent on the structure of the PS and on their ability to produce singlet oxygen. Besides that, the photoactivation efficiency is highly dependent on the cellular sublocalization of the PS and on its cellular uptake and singlet oxygen production. We also found that the resistant cell line B16F10 has distinctive chlorin, isobacteriochlorin, or porphyrin-specific resistance profiles. Furthermore, it is shown that the highly fluorescent chlorin derivative PS2 can also be considered in imaging diagnostics.
Asunto(s)
Melanoma/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ratones , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Porfirinas/química , Porfirinas/efectos de la radiación , Oxígeno Singlete/metabolismoRESUMEN
The synthesis of new porphyrin-indazole hybrids by a Knoevenagel condensation of 2-formyl-5,10,15,20-tetraphenylporphyrin and N-methyl-nitroindazolylacetonitrile derivatives is reported. The target compounds were isolated in moderate to good yields (32-57%) and some of the isolated porphyrin-indazole conjugates showed good performance in the generation of singlet oxygen when irradiated with visible light. Their efficiency as photosensitizers in the photoinactivation of methicillin resistant Staphylococcus aureus-MRSA was evaluated. All derivatives showed to be able to photoinactivate the MRSA bacteria. Compound 3a appears to be the most promising photosensitiser (PS) in the photoinactivation of these bacteria, despite being the least efficient in singlet oxygen generation. The addition of potassium iodide (KI) significantly potentiated the antimicrobial Photodynamic Therapy (aPDT) process mediated by all the analysed porphyrin-indazole conjugates. The combined action of nitroindazole-porphyrins with potassium iodide (KI) action appears to be promising in the photoinactivation of MRSA.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Indazoles/química , Indazoles/farmacología , Porfirinas/química , Porfirinas/farmacología , Antibacterianos/síntesis química , Indazoles/síntesis química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Porfirinas/síntesis química , Oxígeno Singlete/química , Análisis Espectral/métodosRESUMEN
The reaction between organic azides and alkyne derivatives via the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is an efficient strategy to combine phthalocyanines and analogues with different materials. As examples of such materials, it can be considered the following ones: graphene oxide, carbon nanotubes, silica nanoparticles, gold nanoparticles, and quantum dots. This approach is also being relevant to conjugate phthalocyanines with carbohydrates and to obtain new sophisticated molecules; in such way, new systems with significant potential applications become available. This review highlights recent developments on the synthesis of phthalocyanine, subphthalocyanine, and porphyrazine derivatives where CuAAC reactions are the key synthetic step.
Asunto(s)
Azidas/química , Indoles/química , Azidas/síntesis química , Catálisis , Técnicas de Química Sintética , Química Clic , Electrodos , Indoles/síntesis química , Isoindoles , Estructura Molecular , Polímeros/químicaRESUMEN
Novel triazole-porphyrin derivatives (TZ-PORs) were synthesized through the Heck reaction and then incorporated into polyvinylpyrrolidone (PVP) micelles. After verifying that this incorporation did not compromise the photophysical and chemical features of TZ-PORs as photosensitizers, the phototoxicity of the formulations towards cancer cells was screened. Biological studies show high photodynamic activity of all PVP-TZ-POR formulations against a bladder cancer cell line with a particular highlight to PVP-TZ-POR 7e and 7f that are able to significantly reduce HT-1376 cell viability, while they had no effect on control ARPE-19 cells.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Porfirinas/química , Triazoles/química , Animales , Antineoplásicos/síntesis química , Técnicas de Química Sintética , Humanos , Micelas , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Povidona/químicaRESUMEN
Azides and porphyrinoids (such as porphyrin and corrole macrocycles) can give rise to new derivatives with significant biological properties and as new materials' components. Significant synthetic approaches have been studied. A wide range of products (e.g., microporous organic networks, rotaxane and dendritic motifs, dendrimers as liquid crystals, as blood substitutes for transfusions and many others) can now be available and used for several medicinal and industrial purposes.
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Azidas/química , Porfirinas/química , Estructura MolecularRESUMEN
New porphyrin/4-oxoquinoline conjugates were synthesized from the Heck coupling reaction of a ß-brominated porphyrin with 1-allyl-4-oxoquinoline derivatives, followed by demetallation and deprotection affording the promising photosensitizers 9a-e. Singlet oxygen studies have demonstrated that all the porphyrin/4-oxoquinoline conjugates 9a-e were capable of producing cytotoxic species and found to be excellent photosensitizing agents in the inactivation of S. aureus by the antimicrobial photodynamic therapy (aPDT) protocol.
Asunto(s)
4-Quinolonas/farmacología , Antibacterianos/farmacología , Fotoquimioterapia , Porfirinas/farmacología , Staphylococcus aureus/efectos de los fármacos , 4-Quinolonas/química , Antibacterianos/síntesis química , Antibacterianos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Porfirinas/químicaRESUMEN
The post-functionalization of 5,10,15-tris(1-methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin tri-iodide, known as a highly efficient photosensitizer (PS) for antimicrobial photodynamic therapy (aPDT), in the presence of 3- or 4-mercaptobenzoic acid, afforded two new tricationic porphyrins with adequate carboxylic pending groups to be immobilized on chitosan or titanium oxide. The structural characterization of the newly obtained materials confirmed the success of the porphyrin immobilization on the solid supports. The photophysical properties and the antimicrobial photodynamic efficacy of the non-immobilized porphyrins and of the new conjugates were evaluated. The results showed that the position of the carboxyl group in the mercapto units or the absence of these substituents in the porphyrin core could modulate the action of the photosensitizer towards the bioluminescent Gram-negative Escherichia coli bacterium. The antimicrobial activity was also influenced by the interaction between the photosensitizer and the type of support (chitosan or titanium dioxide). The new cationic porphyrins and some of the materials were shown to be very stable in PBS and effective in the photoinactivation of E. coli bacterium. The physicochemical properties of TiO2 allowed the interaction of the PS with its surface, increasing the absorption profile of TiO2, which enables the use of visible light, inactivating the bacteria more efficiently than the corresponding PS immobilized on chitosan.
Asunto(s)
Antibacterianos/química , Quitosano/análogos & derivados , Fármacos Fotosensibilizantes/química , Porfirinas/química , Titanio/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Cationes/síntesis química , Cationes/química , Cationes/farmacología , Quitosano/síntesis química , Quitosano/farmacología , Escherichia coli/efectos de los fármacos , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacología , Porfirinas/síntesis química , Porfirinas/farmacología , Titanio/farmacologíaRESUMEN
The development of selective, efficient, and recoverable/reusable catalysts for oxidation reactions has become one of the main challenges of modern chemistry. Considering our interest in efficient catalytic systems based on porphyrin (Por) and phthalocyanine (Pc) coordination polymers, we report here the synthesis, characterization and catalytic activity of a new Pc coordination polymer (coined hereafter as Cu4CuPcSPy). The new Pc material was obtained in excellent yield, from the reaction of H2PcSPy with an excess amount of copper(ii) acetate. The catalytic efficiency of Cu4CuPcSPy was evaluated in the oxidation of 3,5-di-tert-butylcatechol (3,5-DTBC) in the presence of molecular oxygen from air, with or without the addition of aqueous 30% hydrogen peroxide. The comparison between the homogeneous (CuPcSPy) and the heterogeneous (Cu4CuPcSPy) catalytic systems showed a better performance for the Cu4CuPcSPy material, that can be recovered by filtration and reused, maintaining its activity roughly unchanged during three catalytic cycles. An increment of approximately 30% was also verified in the catalytic activity of the homogeneous and heterogeneous systems by adding aqueous hydrogen peroxide to the catalytic reactions.
RESUMEN
The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N-(2-bromoethyl)nitroindazoles into the corresponding azide. The reactivity in 1,3-dipolar cycloaddition reactions with nitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates was studied with nitroindazoles bearing a vinyl unit. The corresponding nitroindazole-pyrazoline derivatives were obtained in good to excellent yields.
Asunto(s)
Reacción de Cicloadición , Pirazoles/síntesis química , Triazoles/síntesis química , Catálisis , Estructura Molecular , Pirazoles/química , Triazoles/químicaRESUMEN
This review has two parts. The first one gives an approach to interdisciplinary studies against cancer carried out by many scientists using porphyrin-type substrates as photosensitizers in PDT. Intensive studies were performed for almost six decades. The successes really started in 1993 with the first formulation patented under the trade name Photofrin, which was immediately approved in several countries to treat certain types of cancer. Photofrin is still used although certain negative features soon became well known. That has motivated the search for better new photosensitizers. Several ones were developed, evaluated and a few of them had clinical approval. This group includes porphyrin derivatives and pro-drugs (aminolevulinic acid and its alkyl esters). Oncological, dermatological and ophthalmic applications are now taking place for the benefit of mankind. The second part of this review is related with the work carried out in Aveiro at the authors University on the synthesis and biological evaluation of several potential PDT photosensitizers. Not only new synthetic methodologies mainly for porphyrins and chlorins were developed but also other related macrocycles of the phthalocyanine and corrole types have entered in the same "pipeline". In vivo and in vitro biological evaluations also took place under interdisciplinary studies.
Asunto(s)
Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Humanos , Fármacos Fotosensibilizantes/química , Porfirinas/químicaRESUMEN
Cationic derivatives of 5,10,15-tris[4-(pyridin-4-ylsulphanyl)-2,3,5,6-tetrafluorophenyl]-corrolategallium(III)pyridine and 5,10,15-tris[4-(pyridin-2-ylsulfanyl)-2,3,5,6-tetrafluorophenyl]-correlategallium(III)pyridine were synthesized and their photosensitizing properties against the naturally bioluminescent Gram-negative bacterium Allivibrio fischeri were evaluated. The cationic corrole derivatives exhibited antibacterial activity at micromolar concentrations against this Gram-negative bacterium strain.
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Aliivibrio fischeri/efectos de los fármacos , Antibacterianos/farmacología , Luminiscencia , Porfirinas/farmacología , Antibacterianos/química , Cromatografía en Capa Delgada , Ensayo de Unidades Formadoras de Colonias , Pruebas de Sensibilidad Microbiana , Porfirinas/químicaAsunto(s)
Química , Diseño de Fármacos , Personal de Laboratorio , Química/historia , Química/tendencias , Historia del Siglo XXI , HumanosRESUMEN
The synthesis of two triads with two porphyrinyl units linked by oligopyridine derivatives and a new ß-functionalized porphyrin-dihydroazepine is described. One of the porphyrin-oligopyridine triads has a quinquepyridine unit connecting the porphyrins ß-pyrrolic positions, while the other one has an asymmetric quaterpyridine with one of the pyridines fused to the porphyrin. All compounds have fluorescence emission quantum yields in the range of meso-tetraphenylporphyrin (16-22%).