RESUMO
A set of arylazopyrazole-based inhibitors targeting the mitotic motor protein CENP-E was discovered through the chemical platform using the quantitative cyclization of 1,3-diketone intermediate with various hydrazines under mild conditions. Through this efficient platform, the structure-activity relationship pertaining to the pyrazole photoswitch in photoswitchable CENP-E inhibitors not only in vitro but also in cells was successfully clarified.
Assuntos
Proteínas Cromossômicas não Histona , Pirazóis , Ciclização , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Relação Estrutura-Atividade , Humanos , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas Cromossômicas não Histona/metabolismo , Estrutura Molecular , Compostos Azo/química , Compostos Azo/farmacologia , Compostos Azo/síntese química , Relação Dose-Resposta a DrogaRESUMO
The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp2-iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and ß-glucosidase isoenzymes. The most effective derivative reached over a 103-fold higher inhibitory potency towards human ß-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and ß-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach.
Assuntos
Compostos Azo , Inibidores Enzimáticos , Glicosídeo Hidrolases , Glicosídeos , Imino Açúcares , Humanos , Compostos Azo/química , Compostos Azo/farmacologia , Compostos Azo/síntese química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Glicosídeos/química , Glicosídeos/farmacologia , Glicosídeos/síntese química , Imino Açúcares/química , Imino Açúcares/farmacologia , Imino Açúcares/síntese química , Luz , Estrutura Molecular , Relação Estrutura-Atividade , Glucosilceramidase/química , Glucosilceramidase/metabolismo , Glucosilceramidase/farmacologiaRESUMO
1-(3-aryl)-3-(dimethylamino)prop-2-en-1-one (enaminones) derivatives and the diazonium salt of para-chloroaniline were used to synthesize several novel disperse azo dyes with high yield and the use of an environmentally friendly approach. At 100 and 130 °C, we dyed polyester fabrics using the new synthesized disperse dyes. At various temperatures, the dyed fabrics' color intensity was assessed. The results we obtained showed that dyeing utilizing a high temperature method at 130 °C was enhanced than dyeing utilizing a low temperature method at 100 °C. Reusing dye baths once or twice was a way to achieve two goals at the same time. The first was obtaining a dyed product at no cost, and the second was a way to treat the wastewater of dyeing bath effluents and reuse it again. Good results were obtained for the fastness characteristics of polyester dyed with disperse dyes. When the disperse dyes were tested against certain types of microbes and cancer cells, they demonstrated good and encouraging findings for the potential to be used as antioxidants and antimicrobial agents.
Assuntos
Corantes , Poliésteres , Têxteis , Poliésteres/química , Poliésteres/síntese química , Corantes/química , Humanos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Compostos Azo/química , Compostos Azo/síntese química , Testes de Sensibilidade MicrobianaRESUMO
The present work elicits a novel approach to combating COVID-19 by synthesizing a series of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives. The envisaged methodology involves the L-proline-catalyzed condensation of para-amino-functionalized azo benzene, indoline-2,3-dione, and ammonium acetate precursors with pertinent aryl aldehyde derivatives under ultrasonic conditions. The structures of synthesized compounds were corroborated through FT-IR, 1H NMR, 13C NMR, and mass analysis data. Molecular docking studies assessed the inhibitory potential of these compounds against the main protease (Mpro) of SARS-CoV-2. Remarkably, in silico investigations revealed significant inhibitory action surpassing standard drugs such as Remdesivir, Paxlovid, Molnupiravir, Chloroquine, Hydroxychloroquine (HCQ), and (N3), an irreversible Michael acceptor inhibitor. Furthermore, the highly active compound was also screened for cytotoxicity activity against HEK-293 cells and exhibited minimal toxicity across a range of concentrations, affirming its favorable safety profile and potential suitability. The pharmacokinetic properties (ADME) of the synthesized compounds have also been deliberated. This study paves the way for in vitro and in vivo testing of these scaffolds in the ongoing battle against SARS-CoV-2.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Indóis , Simulação de Acoplamento Molecular , Inibidores de Proteases , SARS-CoV-2 , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , SARS-CoV-2/efeitos dos fármacos , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/química , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Células HEK293 , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Simulação por Computador , COVID-19/virologia , Compostos Azo/farmacologia , Compostos Azo/química , Compostos Azo/síntese químicaRESUMO
Hydrazones 1-6, azo-pyrazoles 7-9 and azo-pyrimidines 10-15 are compounds that exhibit antibacterial activity. The mode of action and structures of these derivatives have been previously confirmed as antibacterial. In this investigation, biological screening and molecular docking studies were performed for derivatives 1-15, with compounds 2, 7, 8, 14 and 15 yielding the best energy scores (from -20.7986 to -10.5302 kcal/mol). Drug-likeness and in silico ADME prediction for the most potent derivatives, 2, 7, 8, 14 and 15, were predicted (from 84.46 to 96.85%). The latter compounds showed good recorded physicochemical properties and pharmacokinetics. Compound 8 demonstrated the strongest inhibition, which was similar to the positive control (eflornithine) against Trypanosoma brucei brucei (WT), with an EC50 of 25.12 and 22.52µM, respectively. Moreover, compound 14 exhibited the best activity against Leishmania mexicana promastigotes and Leishmania major promastigotes (EC50 =46.85; 40.78µM, respectively).
Assuntos
Simulação de Acoplamento Molecular , Pirazóis , Pirimidinas , Tripanossomicidas , Trypanosoma brucei brucei , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Leishmania mexicana/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Simulação por Computador , Compostos Azo/farmacologia , Compostos Azo/química , Compostos Azo/síntese química , Relação Estrutura-Atividade , Testes de Sensibilidade ParasitáriaRESUMO
To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and the mechanisms by which BChE affects Alzheimer's disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable BChE inhibitors. The compounds were able to specifically influence different kinetic parameters of the inhibition process by light. For one compound, a 10-fold difference in the IC50-values (44.6 nM cis, 424 nM trans) in vitro was translated to an "all or nothing" response with complete recovery in a murine cognition-deficit AD model at dosages as low as 0.3 mg/kg.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Cognição/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides , Animais , Compostos Azo/síntese química , Compostos Azo/metabolismo , Compostos Azo/efeitos da radiação , Compostos Azo/uso terapêutico , Carbamatos/síntese química , Carbamatos/metabolismo , Carbamatos/efeitos da radiação , Carbamatos/uso terapêutico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/efeitos da radiação , Cinética , Camundongos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/efeitos da radiação , Nootrópicos/síntese química , Nootrópicos/metabolismo , Nootrópicos/efeitos da radiação , Fragmentos de Peptídeos , Ligação Proteica , EstereoisomerismoRESUMO
Light-switchable inhibitors of the enzyme ß-glucocerebrosidase (GCase) have been developed by anchoring a specific azasugar to a dihydroazulene or an azobenzene responsive moiety. Their inhibitory effect towards human GCase, before and after irradiation are reported, and the effect on thermal denaturation of recombinant GCase and cytotoxicity were studied on selected candidates.
Assuntos
Compostos Azo/farmacologia , Azulenos/farmacologia , Inibidores Enzimáticos/farmacologia , Glucosilceramidase/antagonistas & inibidores , Compostos Azo/síntese química , Compostos Azo/química , Azulenos/síntese química , Azulenos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glucosilceramidase/metabolismo , Humanos , Luz , Estrutura Molecular , Processos FotoquímicosRESUMO
Amphiphilic polymers can self-assemble to form nanoparticles with different structures under suitable conditions. Polymer nanoparticles functionalized with aromatic azo groups are endowed with photo-responsive properties. In recent years, a variety of photoresponsive polymers and nanoparticles have been developed based on azobenzene, using different molecular design strategies and synthetic routes. This article reviews the progress of this rapidly developing research field, focusing on the structure, synthesis, assembly and response of photo-responsive polymer assemblies. According to the molecular structure, photo-responsive polymers can be divided into linear polymers containing azobenzene in a side chain, linear polymers containing azobenzene in the main chain, linear polymers containing azobenzene in an end group, branched polymers containing azobenzene and supramolecular polymers containing azobenzene. These systems have broad biomedical application prospects in the field of drug delivery and imaging applications.
Assuntos
Compostos Azo/síntese química , Nanoestruturas/química , Polímeros/síntese química , Compostos Azo/química , Sistemas de Liberação de Medicamentos , Imagem Óptica , Polímeros/químicaRESUMO
Eg5 is a kinesin motor protein that is responsible for bipolar spindle formation and plays a crucial role during mitosis. Loss of Eg5 function leads to the formation of monopolar spindles, followed by mitotic arrest, and subsequent cell death. Several cell-permeable small molecules have been reported to inhibit Eg5 and some have been evaluated as anticancer agents. We now describe the design, synthesis, and biological evaluation of photoswitchable variants with five different pharmacophores. Our lead compound Azo-EMD is a cell permeable azobenzene that inhibits Eg5 more potently in its light-induced cis form. This activity decreased the velocity of Eg5 in single-molecule assays, promoted formation of monopolar spindles, and led to mitotic arrest in a light dependent way.
Assuntos
Compostos Azo/farmacologia , Cinesinas/antagonistas & inibidores , Mitose/efeitos dos fármacos , Compostos Azo/síntese química , Compostos Azo/química , Humanos , Cinesinas/metabolismo , Processos Fotoquímicos , Fuso Acromático/efeitos dos fármacosRESUMO
The ability to control the reactions of highly active chemical species to enable straightforward synthesis of valuable compounds such as bioactive natural products and pharmaceuticals is a continuing challenge in synthetic organic chemistry. This review describes the development of a methodology using reactive metal-carbene species and its synthetic application in our laboratory. First, regioselective synthesis of γ-amino acid equivalents to take advantage of their metal-dependent reactivities and the mechanistic rationale are presented. Chemoselective and enantioselective dearomatization reactions of several arenes with silver-carbene are also discussed. In the second half of the review, we discuss a carbene-insertion reaction into an amide and urea C-N bond for the assembly of nitrogen-bridged cyclic molecules.
Assuntos
Compostos Azo/síntese química , Metais Pesados/química , Compostos Azo/química , Catálise , Metano/análogos & derivados , Metano/químicaRESUMO
Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.
Assuntos
Compostos Azo/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Compostos Azo/síntese química , Compostos Azo/metabolismo , Compostos Azo/efeitos da radiação , Células CHO , Cricetulus , Desenho de Fármacos , Humanos , Ligantes , Luz , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor CB2 de Canabinoide/químicaRESUMO
This article includes the synthesis of heterocyclic azo dye of theophylline by coupling diazonium salt of 4-chloroaniline with theophylline which is, namely, 8-(1-(4-chlorophenyl)azo)theophylline (CPAT). The complexes of cobalt and nickel were prepared by reacting their ions with CPAT ligand in ethanol under 1 : 2 ratio metal-ligand. The CPAT ligand and its complexes were characterized by elemental analysis, infrared spectrometry, electronic absorption spectroscopy, molar conductivity, and magnetic moment. The cobalt and nickel complexes show octahedral geometry having general formula [M(CPAT)2Cl2]. This article addresses the properties of CPAT dye such as photochromic properties. The CPAT dye exhibited obvious and desired changes under irradiation with visible light (405 nm), high sensitive for pH changes which refer to its ability to be analysis indicator. CPAT dye exhibited solvatochromic properties presenting red shift with polar solvent. The CPAT and its complexes show interesting antibiological activities towards Staph. aureus and E. coli bacteria and Aspergillus fungi.
Assuntos
Compostos Azo/síntese química , Teofilina/análogos & derivados , Anti-Infecciosos/farmacologia , Aspergillus/efeitos dos fármacos , Compostos Azo/química , Compostos Azo/farmacologia , Escherichia coli/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Luz , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Teofilina/síntese química , Teofilina/química , Teofilina/farmacologia , Difração de Raios XRESUMO
Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure-activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.
Assuntos
Compostos Azo/uso terapêutico , Fenóis/uso terapêutico , Piridinas/uso terapêutico , Compostos Azo/síntese química , Compostos Azo/química , Imageamento Tridimensional , Fenóis/síntese química , Fenóis/química , Piridinas/síntese química , Piridinas/químicaRESUMO
An effective, potentially scalable asymmetric synthesis of lysergic acid, a core component of the ergot alkaloid family, is reported. The synthesis features the strategic combination of an intramolecular azomethine ylide cycloaddition and Cossy-Charette ring expansion to assemble the target's C- and D-rings. Simple functional group manipulation produced a compound that had been converted to lysergic acid in four steps, thus constituting a formal synthesis of the natural product. The strategy may be used to prepare novel ergot analogues that include unnatural antipodes and may be more amenable to analogue generation relative to prior approaches.
Assuntos
Compostos Azo/síntese química , Ácido Lisérgico/síntese química , Tiossemicarbazonas/síntese química , Compostos Azo/química , Reação de Cicloadição , Ácido Lisérgico/química , Estrutura Molecular , Estereoisomerismo , Tiossemicarbazonas/químicaRESUMO
The first α-boryl diazo compound that is capable of engaging in classic synthetic organic diazo reaction chemistry is described. The diazomethyl-1,2-azaborine 1, which is a BN isostere of phenyldiazomethane, is significantly more stable than phenyldiazomethane; its reaction chemistry ranges from C-H activation, O-H activation, [3+2] cycloaddition, and halogenation, to Ru-catalyzed carbonyl olefination. The demonstrated broad range of reactivity of diazomethyl-1,2-azaborine 1 makes it an exceptionally versatile synthetic building block for the 1,2-azaborine heterocyclic motif.
Assuntos
Compostos Azo/química , Compostos de Boro/química , Compostos Azo/síntese química , Compostos de Boro/síntese química , Complexos de Coordenação/química , Reação de Cicloadição , Esterificação , Halogenação , Rutênio/químicaRESUMO
Nonsteroidal aromatase inhibitors (NSAIs) are well-established drugs for the therapy of breast cancer. However, they display some serious side effects, and their efficacy can be compromised by the development of chemoresistance. Previously, we have reported different indazole-based carbamates and piperidine-sulphonamides as potent aromatase inhibitors. Starting from the most promising compounds, here we have synthesised new indazole and triazole derivatives and evaluated their biological activity as potential dual agents, targeting both the aromatase and the inducible nitric oxide synthase, being this last dysregulated in breast cancer. Furthermore, selected compounds were evaluated as antiproliferative and cytotoxic agents in the MCF-7 cell line. Moreover, considering the therapeutic diversity of azole-based compounds, all the synthesized compounds were also evaluated as antifungals on different Candida strains. A docking study, as well as molecular dynamics simulation, were carried out to shed light on the binding mode of the most interesting compound into the different target enzymes catalytic sites.
Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Compostos Azo/farmacologia , Neoplasias da Mama/tratamento farmacológico , Simulação de Acoplamento Molecular , Micoses/tratamento farmacológico , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Compostos Azo/síntese química , Compostos Azo/química , Candida/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomerâ 1), norbornene grafted with polyethylene glycol, and folic acid (Monomerâ 2) and norbornene attached methyl orange (Monomerâ 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.
Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Ácido Fólico/análogos & derivados , Plásticos/química , Polietilenoglicóis/química , Pró-Fármacos/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Compostos Azo/síntese química , Compostos Azo/química , Compostos Azo/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/síntese química , Clorambucila/química , Clorambucila/toxicidade , Corantes/síntese química , Corantes/química , Corantes/toxicidade , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/toxicidade , Doxorrubicina/síntese química , Doxorrubicina/química , Doxorrubicina/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Ácido Fólico/síntese química , Ácido Fólico/química , Ácido Fólico/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Plásticos/síntese química , Plásticos/toxicidade , Polietilenoglicóis/síntese química , Polietilenoglicóis/toxicidade , Polimerização , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidadeRESUMO
In the present study, a series of azo derivatives (TR-1 to TR-9) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC50 (µg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 µg/mL) compared to the reference drug acarbose (21.59 ± 1.5 µg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor (TR-1) was performed which showed that the compound is a non-competitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.
Assuntos
Antibacterianos/farmacologia , Compostos Azo/farmacologia , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Compostos Azo/síntese química , Compostos Azo/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
Although nitric oxide (NO) has been emerging as a novel local anticancer agent because of its potent cytotoxic effects and lack of off-target side effects, its clinical applications remain a challenge because of the short effective diffusion distance of NO that limits its anticancer activity. In this study, we synthesized albumin-coated poly(lactic-co-glycolic acid) (PLGA)-conjugated linear polyethylenimine diazeniumdiolate (LP/NO) nanoparticles (Alb-PLP/NO NPs) that possess tumor-penetrating and NO-releasing properties for an effective local treatment of melanoma. Sufficient NO-loading and prolonged NO-releasing characteristics of Alb-PLP/NO NPs were acquired through PLGA-conjugated LP/NO copolymer (PLP/NO) synthesis, followed by nanoparticle fabrication. In addition, tumor penetration ability was rendered by the electrostatic adsorption of the albumin on the surface of the nanoparticles. The Alb-PLP/NO NPs showed enhanced intracellular NO delivery efficiency and cytotoxicity to B16F10 murine melanoma cells. In B16F10-tumor-bearing mice, the Alb-PLP/NO NPs showed improved extracellular matrix penetration and spatial distribution in the tumor tissue after intratumoral injection, resulting in enhanced antitumor activity. Taken together, the results suggest that Alb-PLP/NO NPs represent a promising new modality for the local treatment of melanoma.
Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Nanopartículas/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Compostos Azo/síntese química , Compostos Azo/uso terapêutico , Compostos Azo/toxicidade , Bovinos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Melanoma/patologia , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/toxicidade , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/toxicidade , Polietilenoimina/análogos & derivados , Polietilenoimina/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Soroalbumina Bovina/química , Soroalbumina Bovina/toxicidadeRESUMO
Diversity-oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS-compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)-catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo-ß-lactamases (MBLs) NDM-1 and VIM-1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.