RESUMEN

Indolocarbazoles are natural products with a broad spectrum of bioactivity. A distinct feature of indolocarbazole biosynthesis is the modification of the indole and maleimide rings by regioselective tailoring enzymes. Here, we study a new indolocarbazole variant, which is encoded by the acfXODCP genes from Streptomyces venezuelae ATCC 10712. We characterise the pathway by expressing the acfXODCP genes in Streptomyces coelicolor, which led to the production of a C-5/C-5'-dihydroxylated indolocarbazole, which we assign as arcyriaflavin F. We also show that a flavin-dependent monooxygenase AcfX catalyses the C-5/C-5' dihydroxylation of the unsubstituted arcyriaflavin A into arcyriaflavin F. Interestingly, AcfX shares homology to EspX from erdasporine A biosynthesis, which instead catalyses a single C-6 indolocarbazole hydroxylation. In summary, we report a new indolocarbazole biosynthetic pathway and a regioselective C-5 indole ring tailoring enzyme AcfX.

Asunto(s)

Streptomyces , Streptomyces/metabolismo , Streptomyces/genética , Carbazoles/metabolismo , Carbazoles/química , Oxigenasas de Función Mixta/metabolismo , Oxigenasas de Función Mixta/genética , Indoles/metabolismo , Indoles/química

RESUMEN

We introduce a novel and straightforward methodology for photoredox arylation of an indole scaffold using aryldiazonium salts under mild and metal-free conditions. Our approach enables the regioselective and chemoselective introduction of several aryl groups to the C(2) position of indoles and tryptophan, even in competition with other amino acids. This approach extends to the late-stage functionalization of peptides and lysozyme, heralding the unprecedented arylation of tryptophan residues in wild-type proteins and offering broad utility in chemical biology.

Asunto(s)

Indoles , Oxidación-Reducción , Triptófano , Triptófano/química , Indoles/química , Estructura Molecular , Procesos Fotoquímicos , Muramidasa/química , Péptidos/química , Estereoisomerismo , Catálisis

RESUMEN

Chloraluminium phthalocyanine (ClAlPc) has potential therapeutic effect for the treatment of cancer; however, the molecule is lipophilic and may present self-aggregation which limits its clinical success. Thus, nanocarriers like liposomes can improve ClAlPc solubility, reduce off-site toxicity and increase circulation time. For this purpose, developing suitable liposomes requires the evaluation of different lipid compositions. Herein, we aimed to develop liposomes containing soy phosphatidylcholine (SPC), 1,2-distearoyl-sn-glycero- 3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPEPEG2000), cholesterol and oleic acid loaded with ClAlPc using the surface response methodology and the Box-Behnken design. Liposomes with particle size from 110.93 to 374.97 nm and PdI from 0.265 to 0.468 were obtained. The optimized formulation resulted in 69.09 % of ClAlPc encapsulated, with particle size and polydispersity index, respectively, at 153.20 nm and 0.309, providing stability and aggregation control. Atomic force microscopy revealed vesicles in a spherical or almost spherical shape, while the analyzes by Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR) suggested that the drug was adequately incorporated into the lipid bilayer of liposomes, in its amorphous state or molecularly dispersed. In vitro studies conducted in breast cancer cells (4T1) showed that liposome improved phototoxicity compared to the ClAlPc solution. ClAlPc-loaded liposomes also enhanced the production of ROS 3-fold compared to the ClAlPc solution. Finally, confocal microscopy and flow cytometry demonstrated the ability of the liposomes to enter cells and deliver the fluorescent ClAlPc photosensitizer with dose and time-dependent effects. Thus, this work showed that Box-Behnken factorial design was an effective strategy for optimizing formulation development. The obtained ClAlPc liposomes can be applied for photodynamic therapy in breast cancer cells.

Asunto(s)

Neoplasias de la Mama , Indoles , Liposomas , Compuestos Organometálicos , Tamaño de la Partícula , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fotoquimioterapia/métodos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Indoles/química , Indoles/administración & dosificación , Femenino , Compuestos Organometálicos/química , Compuestos Organometálicos/administración & dosificación , Humanos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacología , Línea Celular Tumoral , Polietilenglicoles/química , Fosfatidiletanolaminas/química , Fosfatidilcolinas/química , Colesterol/química , Ácido Oléico/química

RESUMEN

This study introduces a paradigm-shifting approach to optimize mitochondrial targeting. Employing a new fluorescent probe strategy, we unravel a combined influence of both Nernst potential (Ψ) and partitioning (P) contributions. Through the synthesis of new benz[e]indolinium-derived probes, our findings redefine the landscape of mitochondrial localization by optimizing the efficacy of mitochondrial probe retention in primary cortical neurons undergoing normoxia and oxygen-glucose deprivation. This methodology not only advances our understanding of subcellular dynamics, but also holds promise for transformative applications in biomedical research and therapeutic development.

Asunto(s)

Colorantes Fluorescentes , Mitocondrias , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Mitocondrias/metabolismo , Animales , Neuronas/metabolismo , Estructura Molecular , Imagen Óptica , Indoles/química

RESUMEN

Indoles featuring organosulfur compounds serve as privileged structural scaffolds in various biologically active compounds. This study investigates the biological properties of five synthetic sulphenyl vinyl indoles (3 a-e) using both in silico and in vitro methods. Computational analyses employing Swiss ADME and Molinspiration software reveal the remarkable inhibitory activity of compound 3 d against proteases and kinases (scores of 0.18 and 0.06, respectively). Furthermore, it demonstrates the ability to modulate ionic and G protein-coupled receptors (scores: -0.06 and 0.31, respectively) and serves as a ligand for nuclear receptors (score 0.15). In vitro investigations highlight the compounds' efficacy in countering ABTS+ radical attacks and reducing lipid peroxidation levels. Particularly noteworthy is the superior efficacy of compounds 3 a, 3 b, and 3 e in DPPH (EC50 3 a: 268.5 µM) and TEAC assays (EC50 3 a: 49.9 µM; EC50 3 b: 133.4 µM, and EC50 3 e: 84.9 µM), as well as TBARS levels. Compound 3 c significantly reduces acetylcholinesterase activity, positioning itself as a noteworthy enzyme inhibitor. This study emphasizes the versatile biological potential of synthetic indole derivatives, suggesting their applicability for therapeutic purposes.

Asunto(s)

Acetilcolinesterasa , Antioxidantes , Sulfuros , Antioxidantes/química , Acetilcolinesterasa/química , Indoles/farmacología , Indoles/química

RESUMEN

Fragment-based drug discovery is one of the most powerful paradigms in the recent context of medicinal chemistry and is being widely practiced by academic and industrial researchers. Currently, azaindoles are among the most exploited molecular fragments in pharmaceutical innovation projects inspired by fragment-to-lead strategies. The 7-azaindole is the most prominent representative within this remarkable family of pyrrolopyridine fragments, as it is present in the chemical structure of several approved antitumor drugs and also of numerous therapeutic candidates. In this paper, a brief overview on existing proofs of concept in the literature will be presented, as well as some recent works that corroborate 7-azaindole as a privileged and pharmacologically versatile molecular fragment.

Asunto(s)

Antineoplásicos , Descubrimiento de Drogas , Antineoplásicos/farmacología , Química Farmacéutica , Diseño de Fármacos , Indoles/farmacología , Indoles/química

RESUMEN

In this work we will discuss the antiproliferative evaluation and the possible mechanisms of action of indole-thiosemicarbazone compounds LTs with anti-inflammatory activity, previously described in the literature. In this perspective, some analyzes were carried out, such as the study of binding to human serum albumin (HSA) and to biological targets: DNA and human topoisomerase IIα (topo). Antiproliferative study was performed with DU-145, Jukart, MCF-7 and T-47D tumor lines and J774A.1, besides HepG2 macrophages and hemolytic activity. In the HSA interaction tests, the highest binding constant was 3.70 × 106 M-1, referring to LT89 and in the fluorescence, most compounds, except for LT76 and LT87, promoted fluorescent suppression with the largest Stern-Volmer constant for the LT88 3.55 × 104. In the antiproliferative assay with DU-145 and Jurkat strains, compounds LT76 (0.98 ± 0.10/1.23 ± 0.32 µM), LT77 (0.94 ± 0.05/1.18 ± 0.08 µM) and LT87 (0.94 ± 0.12/0.84 ± 0.09 µM) stood out, due to their IC50 values mentioned above. With the MCF-7 and T-47D cell lines, the lowest IC50 was presented by LT81 with values of 0.74 ± 0.12 µM and 0.68 ± 0.10 µM, respectively, followed by the compounds LT76 and LT87. As well as the positive control amsacrine, the compounds LT76, LT81 and LT87 were able to inhibit the enzymatic action of human Topoisomerase IIα.

Asunto(s)

Antineoplásicos , Tiosemicarbazonas , Humanos , Simulación del Acoplamiento Molecular , Antineoplásicos/farmacología , Antineoplásicos/química , Relación Estructura-Actividad , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Línea Celular Tumoral , Inhibidores de Topoisomerasa II/farmacología , ADN/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Indoles/farmacología , Indoles/química , Proliferación Celular

RESUMEN

Melanosomes have been considered crucial targets in melanoma treatments. In this study we explored the role of melanosomes in photodynamic therapy (PDT), employing the synthetic Zn(II) phthalocyanine Pc13, a potent photosensitizer that promotes melanoma cell death after irradiation. Phototoxic action is mediated by reactive oxygen species increase. The internalization mechanism of Pc13 and its consequent subcellular localization were evaluated in melanotic B16-F0 cells. Pharmacological inhibitors of dynamin or caveolae, but not of clathrin, decreased Pc13 cellular uptake and phototoxicity. Similar results were obtained when cells over-expressed dominant negative mutants of dynamin-2 and caveolin-1, indicating that Pc13 is internalized by caveolae-mediated endocytosis. Confocal microscopy analysis revealed that Pc13 targets melanosomes and damage of these structures after irradiation was demonstrated by transmission electron microscopy. Treatment of pigmented B16-F0 and WM35 melanoma cells with the melanin synthesis inhibitor phenylthiourea for 48 h led to cell depigmentation and enhanced cell death after irradiation, whereas a 3-h period of inhibition did not modify melanin content but produced a marked reduction of Pc13 phototoxicity, together with a decrease of oxidative melanin synthesis intermediates. In contrast, the effect of Pc13 in amelanotic A375 cells was not altered by phenylthiourea treatment. These results provide evidence that melanosomes have a dual role in the efficacy of PDT. While melanin antagonizes the phototoxic action of Pc13, the release of cytotoxic synthetic intermediates to cytosol after irradiation and melanosome damage is conducive to the phototoxic response. Based on these findings, we demonstrate that melanosome-targeted PDT could be an effective approach for melanoma treatment.

Asunto(s)

Dermatitis Fototóxica , Melanoma , Caveolina 1/metabolismo , Caveolina 1/farmacología , Caveolina 1/uso terapéutico , Endocitosis , Humanos , Indoles/química , Isoindoles , Melaninas/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanosomas/metabolismo , Melanosomas/ultraestructura , Feniltiourea/metabolismo , Feniltiourea/farmacología , Feniltiourea/uso terapéutico

RESUMEN

Phthalocyanines are photosensitizers activated by light at a specific wavelength in the presence of oxygen and act through the production of Reactive Oxygen Species, which simultaneously attack several biomolecular targets in the pathogen agent and, therefore, have multiple and variable action sites. This nonspecific action site bypasses conventional resistance mechanisms. Antimicrobial Photodynamic Therapy (aPDT) is safe, easy to implement and, unlike conventional agents, may have a wide activity spectrum of photoantimicrobials. This work is a systematic review of the literature based on nanocarriers containing phthalocyanines in aPDT against bacteria, fungi, viruses, and protozoa. The search was performed in two different databases (MEDLINE/PubMed and Web of Science) between 2011 and May 2021. Nanocarriers often improve the action or are equivalent to free drugs, but their use allows substituting the organic solvent in the case of hydrophobic phthalocyanines, allowing for a safer application of aPDT with the possibility of prolonged release. In the case of hydrophilic phthalocyanines, they would allow for nonspecific site delivery with a possibility of cellular internalization. A single infectious lesion can have multiple microorganisms, and PDT with phthalocyanines is an interesting treatment given its ample spectrum of action. It is possible to highlight the upconversion nanosystems, which allow for the activation of phthalocyanine in deeper tissues by using longer wavelengths, as a system that has not yet been studied, but which could provide treatment solutions. The use of nanocarriers containing phthalocyanines requires more study to establish the use of aPDT in humans.

Asunto(s)

Antiinfecciosos , Fotoquimioterapia , Antibacterianos/uso terapéutico , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Humanos , Indoles/química , Indoles/farmacología , Isoindoles , Nanotecnología , Preparaciones Farmacéuticas , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico

RESUMEN

Phthalocyanine derivatives have been proposed as photosensitizers for the treatment of several microbial infections. In this review, the progress in the structures of phthalocyanines was analyzed, considering that these compounds can easily functionalize and can form complexes with various metal ions. In this sense, different substituents were used to increase the interaction with the microorganisms, improving their photodynamic inactivation. Furthermore, these photosensitizers absorb strongly at phototherapeutic window, emit red fluorescence, and efficiently produce the formation of reactive oxygen species. Subsequently, the influence of binding, bacteria types, cell density, washing effect, and media on photoinactivation was remarked to elimination of microbes. Finally, photokilling of bacterial biofilm by phthalocyanines and the mechanism of action were discussed. Therefore, this review brings together the main features of phthalocyanines as antimicrobial phototherapeutic agents.

Asunto(s)

Antiinfecciosos , Fotoquimioterapia , Bacterias , Indoles/química , Indoles/farmacología , Isoindoles , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología

RESUMEN

Caulerpin is a bisindolic alkaloid that has been obtained from many species of the genus Caulerpa. The main objective of this paper is to evaluate four extraction methods of caulerpin in the C. racemosa: maceration (DMA), Soxhlet extraction (SOX), ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE). The methods were compared through caulerpin content quantified by Ultraviolet-visible (UV-vis) spectrophotometry. The highest extract yield was obtained by SOX but the highest contain of caulerpin was presented in the MAE extract. The caulerpin content was significant different within the extacts by MAE and UAE, it yielded by MAE more than three times as much as UAE. The most efficient caulerpin extraction method had the parameters solvent, temperature and time optimised. Thus, the best conditions were achieved with MAE in ethanol during 7 min at 90 °C. Therefore, this work suggests an improved routine analysis of caulerpin by the green chemistry concept.

Asunto(s)

Caulerpa , Caulerpa/química , Indoles/química , Microondas , Solventes/química

RESUMEN

This work aimed to develop a simple and low-cost method to obtain human serum albumin (HSA) and its consequent application for in vitro drug interaction assays. The HSA was purified by classic principles of plasma precipitation and thermocoagulation, using a multiple-stage fractionation. The quality of the final product was assessed by electrophoresis, protein dosage by the Lowry method and the pharmacopeial thermal stability. At the end, an isotonic solution of HSA with a total protein concentration of 2.7 mg·mL-1 was obtained, which was visualized as a single band corresponding to the molecular weight of 66 kDa. After the thermal stability test, there was no indication of turbidity or color change of the solution. Finally, the HSA was useful for interaction assays with indole-thiazole and indole-thiazolidinone derivatives through UV-vis absorption and fluorescence spectroscopic studies, as well as by docking molecular analysis. Derivatives quenched the intrinsic fluorescence of HSA, disrupted the tryptophan residues microenvironment, and probably bind at Sudlow's site I. Therefore, the simplified methodology developed in this work proved to be effective in obtaining HSA that can be applied to research goals including drug interaction assays.

Asunto(s)

Indoles/química , Albúmina Sérica Humana/química , Tiazoles/química , Sitios de Unión , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica , Espectrometría de Fluorescencia , Termodinámica

RESUMEN

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome, and currently no effective targeted therapies are available. Indole compounds have been shown to have potential antitumor activity against various cancer cells. In the present study, we found that new four benzo[f]indole-4,9-dione derivatives reduce TNBC cell viability by reactive oxygen species (ROS) accumulation stress in vitro. Further analyses showed that LACBio1, LACBio2, LACBio3 and LACBio4 exert cytotoxic effects on MDA-MB 231 cancer cell line by inducing the intrinsic apoptosis pathway, activating caspase 9 and Bax/Bcl-2 pathway in vitro. These results provide evidence that these new four benzo[f]indole-4,9-dione derivatives could be potential therapeutic agents against TNBC by promoting ROS stress-mediated apoptosis through intrinsic-pathway caspase activation.

Asunto(s)

Antineoplásicos , Apoptosis/efectos de los fármacos , Citotoxinas , Indoles , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Citotoxinas/síntesis química , Citotoxinas/química , Citotoxinas/farmacología , Femenino , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo

RESUMEN

A possible inhibitor of proteases, which contains an indole core and an aromatic polar acetylene, was designed and synthesized. This indole derivative has a molecular architecture kindred to biologically relevant species and was obtained through five synthetic steps with an overall yield of 37% from the 2,2'-(phenylazanediyl)di(ethan-1-ol). The indole derivative was evaluated through docking assays using the main protease (SARS-CoV-2-Mpro) as a molecular target, which plays a key role in the replication process of this virus. Additionally, the indole derivative was evaluated as an inhibitor of the enzyme kallikrein 5 (KLK5), which is a serine protease that can be considered as an anticancer drug target.

Asunto(s)

Acetileno/química , Antivirales/química , Antivirales/síntesis química , Indoles/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , SARS-CoV-2/enzimología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Calicreínas/antagonistas & inhibidores , Modelos Moleculares , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/farmacología , SARS-CoV-2/efectos de los fármacos , Tratamiento Farmacológico de COVID-19

RESUMEN

Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date. Herein we describe the synthesis and evaluation of two series of indole- and N-phenylpyrazole-GA derivatives (4a-f and 5a-f). We measured their inhibitory activity and enzyme kinetics against PTP1B using p-nitrophenylphosphate (pNPP) assay. GA derivatives bearing substituted indoles or N-phenylpyrazoles fused to their A-ring showed a 50% inhibitory concentration for PTP1B in a range from 2.5 to 10.1 µM. The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC50 = 2.5 µM) than that of positive controls ursolic acid (IC50 = 5.6 µM), claramine (IC50 = 13.7 µM) and suramin (IC50 = 4.1 µM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds.

Asunto(s)

Inhibidores Enzimáticos , Ácido Glicirretínico , Indoles , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Pirazoles , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/síntesis química , Ácido Glicirretínico/química , Humanos , Indoles/síntesis química , Indoles/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad

RESUMEN

Photobiomodulation (PBM) is a promising medical treatment modality in the area of photodynamic therapy (PDT). In this study, we investigated the effect of combined therapy in a 3D microenvironment using aluminum chloride phthalocyanines (AlClPc) as the photosensitizing agent. Normal human fibroblast-containing collagen biomatrix was prepared and treated with an oil-in-water (o/a) AlClPc-loaded nanoemulsion (from 0.5 to 3.0 µM) and irradiated at a range of fluences (from 0.1 to 3.0 J/cm2) using a continuous-wave light-emitting diode (LED) irradiation system (660 nm). PBM at 1.2 J/cm2 and AlClPc/NE at 0.5 µM modified the fibroblast signaling response under 3D conditions, promoting collagen synthesis, ROS production, MMP-9 secretion, proliferation of the actin network, and facile myofibroblastic differentiation. PBM alone (at 1.2 J/cm2 and 0.3 J/cm2) had no significant effect on any of these parameters. The combined therapy affected myofibroblastic differentiation, inflammatory response, and extracellular matrix pliability, and should thus be examined further in subsequent studies considering that no side effects of PBM have been reported. Even though significant progress has been made in the field of phototherapy in recent years, it is necessary to further elucidate the detailed mechanisms underlying its effects already shown in 2D conditions to increase the acceptance of this beneficial and non-invasive therapeutic approach.

Asunto(s)

Cloruro de Aluminio/farmacología , Fibroblastos/efectos de los fármacos , Indoles/farmacología , Luz , Compuestos Organometálicos/farmacología , Fármacos Fotosensibilizantes/farmacología , Cloruro de Aluminio/química , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Células Cultivadas , Colágeno/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Humanos , Indoles/química , Metaloproteinasa 9 de la Matriz/metabolismo , Compuestos Organometálicos/química , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

A novel tricationic Zn(II)phthalocyanine derivative, (NCH3)3ZnPc3+, was synthesized by ring expansion reaction of boron(III) [2,9(10),16(17)-trinitrosubphthalocyaninato]chloride. First, the reaction of this subphthalocyanine with 2,3-naphthalenedicarbonitrile and Zn(CH3COO)2 catalyzed by 8-diazabicyclo[5.4.0]undec-7-ene was used to obtain the A3B-type nitrophthalocyanine. After reduction of nitro groups with Na2S and exhaustive methylation of amino groups, (NCH3)3ZnPc3+ was formed in good yields. In addition, the tetracationic analog (NCH3)4ZnPc4+ was synthesized to compare their properties. The absorption and fluorescence spectra showed the Q-bands and the red emission, respectively, which are characteristic of the Zn(II)phthalocyanine derivatives in N,N-dimethylformamide. Furthermore, photodynamic activity sensitized by these compounds was studied in the presence of different molecular probes to sense the formation of reactive oxygen species. (NCH3)3ZnPc3+ efficiently produced singlet molecular oxygen and also it sensitized the formation of superoxide anion radical in the presence of NADH, while the photodynamic activity of (NCH3)4ZnPc4+ was very poor, possibly due to the partial formation of aggregates. Furthermore, the decomposition of L-tryptophan induced by (NCH3)3ZnPc3+ was mainly mediated by a type II mechanism. Antimicrobial photodynamic inactivation sensitized by these phthalocyanines was evaluated in Staphylococcus aureus, Escherichia coli, and Candida albicans, as representative microbial cells. In cell suspensions, (NCH3)3ZnPc3+ was rapidly bound to microbial cells, showing bioimages with red fluorescence emission. After 5 min of irradiation with visible light, (NCH3)3ZnPc3+ was able to completely eliminate S. aureus, E. coli and C. albicans, using 1.0, 2.5 and 5.0 µM phthalocyanine, respectively. In contrast, a low photoinactivation activity was found with (NCH3)4ZnPc4+ as a photosensitizer. Therefore, the amphiphilic tricationic phthalocyanine (NCH3)3ZnPc3+ is a promising photosensitizing structure for application as a broad-spectrum antimicrobial phototherapeutic agent.

Asunto(s)

Antiinfecciosos/farmacología , Indoles/farmacología , Compuestos Organometálicos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Tensoactivos/farmacología , Antiinfecciosos/química , Candida albicans/efectos de los fármacos , Cationes/química , Cationes/farmacología , Escherichia coli/efectos de los fármacos , Indoles/química , Isoindoles , Pruebas de Sensibilidad Microbiana , Compuestos Organometálicos/química , Fármacos Fotosensibilizantes/química , Staphylococcus aureus/efectos de los fármacos , Tensoactivos/química , Compuestos de Zinc

RESUMEN

Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzheimer's disease (AD). l-Hypaphorine (l-HYP) is a natural indole alkaloid that has been shown to have effects on the central nervous system (CNS). The goal of this research was to synthesize l-HYP and d-HYP and test their anticholinesterasic properties in rat brain regions. l-HYP suppressed acetylcholinesterase (AChE) activity only in the cerebellum, whereas d-HYP inhibited AChE activity in all CNS regions studied. No cytotoxic effect on normal human cells (HaCaT) was observed in the case of l-HYP and d-HYP although an increase in cell proliferation. Molecular modeling studies revealed that d-HYP and l-HYP have significant differences in their binding mode positions and interact stereospecifically with AChE's amino acid residues.

Asunto(s)

Acetilcolinesterasa/metabolismo , Encéfalo/enzimología , Inhibidores de la Colinesterasa/farmacología , Indoles/farmacología , Animales , Encéfalo/patología , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Indoles/química , Estructura Molecular , Ratas , Relación Estructura-Actividad

RESUMEN

We report a selective, mild, and efficient C-H functionalization of tryptophan and tryptophan-containing peptides with activated α-bromo-carbonyl compounds under visible-light irradiation. The protocol efficiency is outlined by the wide substrate scope and excellent tolerance of sensitive functional groups present in the amino acid side chains. The method can be successfully extended to access pharmaco-peptide conjugate scaffolds.

Asunto(s)

Indoles/química , Péptidos/química , Triptófano/química , Alquilación , Catálisis , Estructura Molecular , Procesos Fotoquímicos

RESUMEN

Breast cancer is the most common neoplasm among women but thanks to innovative therapies, patients' prognosis has considerably improved. In this aspect, nanotechnology has been applied for cancer therapy aiming to reduce its usual side effects. In this study we aimed to evaluate the effects of nanoemulsions containing photosensitizer and chemotherapeutic agents associated with photodynamic therapy in a breast cancer in vivo model. Our results showed that synergistic treatments in which chloroaluminum phthalocyanine (NE-Pc) administered together with Doxorubicin (Dox) in the presence of laser irradiation (NE-PcDoxo + PDT) led to a reduction of 4 T1 induced breast cancer in mice, decline of tumor VEGF expression, increase in Caspase-3 expression, tissue necrosis and massive decrease in proliferative cells, as shown by Ki67 immunostaining. Furthermore, this associated treatment induced overexpression of apoptotic genes ABL1, CD70, CRADD, FASL, and NME5 and a reduction in expression of anticancer drug target genes CDK2, ERBB2, FIGF, IGF2, PARP4 and PGR. These results validate this treatment as a promising alternative to improve the currently applied anticancer strategies.

Asunto(s)

Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Doxorrubicina/química , Indoles/química , Nanocápsulas/química , Compuestos Organometálicos/química , Fármacos Fotosensibilizantes/química , Animales , Antineoplásicos/farmacología , Caspasa 3/genética , Caspasa 3/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Doxorrubicina/farmacología , Descubrimiento de Drogas , Quimioterapia Combinada , Emulsiones/química , Femenino , Humanos , Indoles/farmacología , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales , Compuestos Organometálicos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo