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1.
J Colloid Interface Sci ; 558: 47-54, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31580954

RESUMO

The unique antibacterial characteristics of Ag nanomaterials offer a wide potential range of applications, but achieving rapid and durable antibacterial efficacy is challenging. This is because the speed and durability of the antibacterial function make conflicting demands on the structural design: the former requires the direct exposure of Ag to the surrounding environment, whereas the durability requires Ag to be protected from the environment. To overcome this incompatibility, we synthesize sandwich-structured polydopamine shells decorated both internally and externally with Ag nanoparticles, which exhibit prompt and lasting bioactivity in applications. These shells are biocompatible and can be used in vivo to counter bacterial infection caused by methicillin-resistant Staphylococcus aureus superbugs and to inhibit biofilm formation. This work represents a new paradigm for the design of composite materials with enhanced antibacterial properties.


Assuntos
Antibacterianos/química , Materiais Biocompatíveis/química , Indóis/química , Nanopartículas Metálicas/química , Polímeros/química , Prata/química , Animais , Antibacterianos/farmacologia , Materiais Biocompatíveis/farmacologia , Escherichia coli/efeitos dos fármacos , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley
2.
J Photochem Photobiol B ; 201: 111684, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31733505

RESUMO

Since the beginning of life on Earth, cyanobacteria have been exposed to natural ultraviolet-A radiation (UV-A, 315-400 nm) and ultraviolet-B radiation (UV-B, 280-315 nm), affecting their cells' biomolecules. These photoautotrophic organisms have needed to evolve to survive and thus, have developed different mechanisms against ultraviolet radiation. These mechanisms include UVR avoidance, DNA repair, and cell protection by producing photoprotective compounds like Scytonemin, carotenoids, and Mycosporine-like amino acids (MAAs). Lyngbya marine species are commercially important due to their secondary metabolites that show a range of biological activities including antibacterial, insecticidal, anticancer, antifungal, and enzyme inhibitor. The main topic in this review covers the Lyngbya sp., a cyanobacteria genus that presents photoprotection provided by the UV-absorbing/screening compounds such as MAAs and Scytonemin. These compounds have considerable potentialities to be used in the cosmeceutical, pharmaceutical, biotechnological and biomedical sectors and other related manufacturing industries with an additional value of environment friendly in nature. Scytonemin has UV protectant, anti-inflammatory, anti-proliferative, and antioxidant activity. MAAs act as sunscreens, provide additional protection as antioxidants, can be used as UV protectors, activators of cell proliferation, skin-care products, and even as photo-stabilizing additives in paints, plastics, and varnishes. The five MAAs identified so far in Lyngbya sp. are Asterina-330, M-312, Palythine, Porphyra-334, and Shinorine are capable of dissipating absorbed radiation as harmless heat without producing reactive oxygen species.


Assuntos
Aminoácidos/química , Cianobactérias/metabolismo , Cicloexanóis/química , Indóis/química , Fenóis/química , Protetores Solares/química , Raios Ultravioleta , Aminoácidos/isolamento & purificação , Antioxidantes/química , Cicloexanóis/isolamento & purificação , Indóis/isolamento & purificação , Fenóis/isolamento & purificação , Protetores Solares/metabolismo
3.
Nature ; 575(7782): 336-340, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723273

RESUMO

Organoboron reagents are important synthetic intermediates that have a key role in the construction of natural products, pharmaceuticals and organic materials1. The discovery of simpler, milder and more efficient approaches to organoborons can open additional routes to diverse substances2-5. Here we show a general method for the directed C-H borylation of arenes and heteroarenes without the use of metal catalysts. C7- and C4-borylated indoles are produced by a mild approach that is compatible with a broad range of functional groups. The mechanism, which is established by density functional theory calculations, involves BBr3 acting as both a reagent and a catalyst. The potential utility of this strategy is highlighted by the downstream transformation of the formed boron species into natural products and drug scaffolds.


Assuntos
Compostos de Boro/química , Compostos de Boro/síntese química , Boro/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Teoria da Densidade Funcional , Descoberta de Drogas , Indóis/química , Compostos Organometálicos/química , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química
4.
Int J Nanomedicine ; 14: 7079-7093, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564866

RESUMO

Background: Currently, effective detection and treatment of cutaneous malignant melanoma (CMM) still face severe challenges. Ultrasound molecular imaging as a noninvasive and easy-to-operate method is expected to bring improvements for tumor detection. Purpose: The aim of this research is to prepare novel phase-change ultrasound contrast agents, Nds-IR780, which can perform not only dual-mode molecule-targeted imaging but also targeted photothermal therapy for CMM. Methods: A double emulsion process was used to prepare the Nds-IR780. Then, the entrapment rate and drug loading of IR-780 iodide in Nds-IR780 were detected by high-performance liquid chromatography. The biocompatibility of Nds-IR780 was evaluated by a CCK-8 assay and the characteristics and stability of that were verified through the particle size analyzer, laser scanning confocal microscopy (LSCM) and transmission electron microscopy (TEM). The abilities of dual-mode molecule-targeted imaging and targeted photothermal therapy for Nds-IR780 were confirmed via the in vitro and in vivo experiments. Results: Nds-IR780 had good size distribution, polydispersity index, stability and biosafety. The in vitro and in vivo experiments confirmed that Nds-IR780 were capable of targeting CMM cells with high affinity (22.4±3.2%) and facilitating dual-mode imaging to detect the primary lesion and sentinel lymph nodes (SLNs) of CMM. Furthermore, the photothermal ablation of CMM mediated by Nds-IR780 was very effective in vivo. Conclusion: The newly prepared Nds-IR780 were observed to be effective targeted theranostic probe for the precise detection and targeted treatment of CMM.


Assuntos
Meios de Contraste/química , Gotículas Lipídicas/química , Melanoma/diagnóstico , Melanoma/terapia , Nanopartículas/química , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Nanomedicina Teranóstica , Animais , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Humanos , Hipertermia Induzida , Indóis/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia , Temperatura Ambiente , Distribuição Tecidual , Carga Tumoral , Ultrassom
5.
Int J Nanomedicine ; 14: 7141-7153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564870

RESUMO

Background: Theranostics, elaborately integrating both therapeutic and diagnostic functions into a nanoplatform holds great potential for precision cancer medicine. Methods: Herein, a biodegradable theranostic nanoplatform with hyperthermia-induced bubble ability for highly efficient ultrasound (US) imaging-guided chemo-photothermal therapy of breast tumors was developed. The prepared nanoparticles consisted of polydopamine (PDA)-modified hollow mesoporous organosilica nanoparticles (HMONs) with approximately 75 nm in diameter for doxorubicin (DOX) loading and perfluoropentane (PFP) filling. In addition, the pH-sensitive PDA coating served as both gatekeeper controlling DOX release and photothermal agent for inducing hyperthermia. Results: Such nanoplatform (PDA@HMONs-DOX/PFP, PHDP) provides efficient loading (328 mg/g) and controllable stimuli-responsive release of DOX for chemotherapy. The incorporated disulfide bonds in the framework of HMONs endowed nanoparticles with intrinsic glutathione-responsive biodegradability and improved biocompatibility. Benefiting from the hyperthermia upon an 808-nm laser irradiation of PDA, the liquid-gas phase transition of the loaded PFP was induced, resulting in the generation of the nanobubbles, followed by the coalescence into microbubbles. This conversation could enhance the tumor cell uptake of nanoparticles, as well as intensify the US imaging signals. In addition, a synergistic therapeutic effect of our fabricated nanoplatform on cells/tumor growth effect has been systematically evaluated both in vitro and in vivo. Conclusion: Therefore, such "all-in-one" PHDP nanoparticles with satisfactory biocompatibility and biodegradability, hyperthermia-induced bubble ability and simultaneous US imaging performance hold great potential for cancer nanotheranostics.


Assuntos
Hipertermia Induzida , Microbolhas , Nanopartículas/química , Fototerapia , Nanomedicina Teranóstica , Ultrassonografia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Feminino , Humanos , Indóis/química , Cinética , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Polímeros/química , Distribuição Tecidual/efeitos dos fármacos
6.
Int J Nanomedicine ; 14: 7155-7171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564871

RESUMO

Background: Platelet activation and subsequent aggregation are the initial stages of thrombosis. A molecular probe that specifically targets activated platelets and remains retained under high shear stress in vivo can enhance the imaging effect to achieve early and accurate diagnosis. Methods and materials: In this study, we constructed nanoparticles (NPs) using polydopamine to carry two peptides that simultaneously bind integrin αIIbß3 and P-selectin on activated platelets to enhance the targeting of NPs to thrombus. Results: The targeting specificity and binding stability of the NPs on red and white thrombi were demonstrated in vitro using a simulated circulatory device and the targeting effect of the NPs on mixed thrombus was studied by  magnetic resonance (MR)/photoacoustic (PA) dual-modality imaging in vivo. NPs that were surface modified with both peptides have higher selectivity and retention to red and white thrombi in vitro than NPs with a single or no peptide, and the targeting effect was closely related to the number and distribution of activated platelets as well as the structure and type of thrombus. The NPs also have MR/PA dual-modality imaging functionality, significantly enhancing the imaging of mixed thrombus in vivo. Conclusion: These dual-targeted NPs have improved targeting specificity and binding stability to different thrombi under high shear stress and are beneficial for the early diagnosis of thrombosis.


Assuntos
Indóis/química , Imagem por Ressonância Magnética , Nanopartículas/química , Técnicas Fotoacústicas , Polímeros/química , Trombose/diagnóstico por imagem , Animais , Meios de Contraste/química , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Imagem Molecular , Nanopartículas/ultraestrutura , Ativação Plaquetária , Ratos Sprague-Dawley
7.
Chem Commun (Camb) ; 55(77): 11619-11622, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31501844

RESUMO

Mesoporous organosilica nanoparticles (PHT-PMO) have been prepared from an octa-triethoxysilylated Zn phthalocyanine precursor. These PHT-PMO nanoparticles had no dark toxicity but high phototoxicity when irradiated at 650 nm, and remarkable near-infrared phototoxicity when excited at 760 and 810 nm. The PHT-PMO were then aminated to promote electrostatic complexation with siRNA. Transfection experiments were performed upon NIR irradiation and photochemical internalization was very efficient, leading to 65% luciferase extinction in MCF-7 cancer cells expressing stable luciferase.


Assuntos
Indóis/química , Nanopartículas/química , Compostos Organometálicos/química , Fotoquimioterapia/métodos , RNA Interferente Pequeno/química , Silanos/química , Sobrevivência Celular , Cetrimônio/química , Humanos , Raios Infravermelhos , Luciferases/genética , Células MCF-7 , Processos Fotoquímicos , Porosidade , RNA Interferente Pequeno/metabolismo , Eletricidade Estática , Propriedades de Superfície
8.
Chem Biol Interact ; 312: 108816, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505164

RESUMO

Indirubins E804 (indirubin-3'-(2,3 dihydroxypropyl)-oximether) and 7BIO (7-Bromoindirubin-3'-oxime) are synthetic derivatives of natural indirubin, the active compound in Danggui Longhui Wan, a traditional Chinese remedy for cancer and inflammation. Herein, we explore E804 and 7BIO for their potential to modulate key pro-inflammatory genes and cytokines in LN-18 and T98G glioblastoma cells. High grade gliomas typically secrete large amounts of inflammatory cytokines and growth factors that promote tumor growth in an autocrine fashion. Inflammation is emerging as a key concern in the success of new treatment modalities for glioblastomas. Studies indicate that select indirubin derivatives bind and activate signaling of the AHR pathway, as well as inhibit cyclin-dependent kinases and STAT3 signaling. AHR signaling is involved in hematopoiesis, immune function, cell cycling, and inflammation, and thus may be a possible target for glioma treatment. To determine the significance of the AHR pathway in LN-18 and T98G glioma inflammatory profiles, and on the effects of E804 and 7BIO on these profiles, we used 6,2',4'-trimethoxyflavone (TMF), a putative selective AHR antagonist. It was confirmed that E804 and 7BIO activates the AHR leading to cyp1b1 expression, and that TMF antagonizes expression. We then employed a commercial cancer inflammation and immunity crosstalk qRT-PCR array to screen for anti-inflammatory related properties. TMF alone inhibited expression of ifng, ptsg2, il12b, tnfa, il10, il13, the balance between pd1 and pdl1, and even expression of mhc1a/b. E804 was very potent in suppressing many pro-inflammatory genes, including il1a, il1b, il12a, ptgs2, tlr4, and others. E804 also affected expression of il6, vegfa, and stat3. Conversely, 7BIO induced cox2, but suppressed a different selection of pro-inflammatory genes including nos2, tnfa, and igf1. Secretion of IL-6 protein, an iconic inflammatory cytokine, was decreased by E804. VEGF (vascular endothelial growth factor) protein secretion was upregulated by 7BIO, yet downregulated by E804 and E804 plus TMF. Thus, E804 is both an AHR ligand and regulator of important pro-inflammatory cytokines such as IL-6 and oncogene STAT3, among others. Our results point to the use of E804 and TMF in combination as a promising new treatment for glioblastoma.


Assuntos
Indóis/farmacologia , Oximas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Citocinas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Indóis/química , Oximas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Phys Chem Chem Phys ; 21(32): 17971-17977, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31384846

RESUMO

The electron-hole injection from a family of spiropyran photoswitches into A/T-duplex DNA has been investigated at the molecular level for the first time. Multiscale computations coupled with automatized quantitative wavefunction analysis reveal a pronounced directionality and regioselectivity towards the template strand of the duplex DNA. Our findings suggest that this directional and regioselective photoinduced electron-hole transfer could thus be exploited to tailor the charge transport processes in DNA in specific applications.


Assuntos
Benzopiranos/química , DNA/química , Indóis/química , Substâncias Intercalantes/química , Nitrocompostos/química , Transporte de Elétrons , Luz , Modelos Moleculares , Conformação de Ácido Nucleico , Oxirredução , Processos Fotoquímicos , Prótons , Termodinâmica
10.
Eur J Med Chem ; 181: 111570, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408809

RESUMO

Despite the success achieved in the treatment of acute lymphoblastic leukemia (ALL), the search for new drugs featuring selectivity against leukemia cells and effectiveness to prevent relapsed ALL is still highly desirable. Here, we described the synthesis of several novel 3-substituted and 3,6-disubstituted-2-carboalkoxy indoles followed by the elucidation of their mechanism of action and in vivo anti-leukemia efficacy. The synthesis of 3-substituted-2-carboalkoxy indoles relied on two Heck arylations of methyl acrylate and methyl cinnamates respectively, to generate ß,ß-disubstituted acrylates followed by an efficient Cadogan-Sundberg reaction of these latter intermediates. The method developed led to the synthesis of twenty-one novel functionalized indoles. Of these, indole 20 showed selective cytotoxicity against leukemia cells at the nanomolar scale, and, therefore, it was selected for the investigation of its mechanism of action. Indole 20 was found to target tubulin leading to G2/M cell cycle arrest, DNA damage and apoptosis. Indole 20 decreased ß-tubulin protein in leukemia cells in a time-dependent manner and induced depolymerization of the microtubule network in Hela cells, thus fully characterizing its microtubule destabilizer activity. The connectivity map analysis of HL60 promyelocytic leukemia cells treated with indole 20 revealed a transcriptional profile similar to that of cells treated with prostaglandins, apparently due to the induction of cellular differentiation as addressed by the expression of CD11 and CD14 markers. Finally, indole 20 given intraperitoneally, at 10 mg/kg, 5x/week significantly prolonged the overall survival of NOD/SCID mice transplanted with RS4; 11 B-ALL cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Indóis/química , Indóis/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Cinamatos/síntese química , Cinamatos/química , Cinamatos/uso terapêutico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HL-60 , Células HeLa , Humanos , Indóis/síntese química , Camundongos Endogâmicos NOD , Camundongos SCID
11.
Chem Commun (Camb) ; 55(67): 9971-9974, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31367709

RESUMO

Photodynamic therapy (PDT) is a clinically approved cancer treatment that uses light, oxygen and a photosensitizer to produce localized reactive oxygen species (ROS). Due to the short lifetime of ROS, the location of the photosensitizer in the cell is believed to be the key determinant governing the outcome of PDT. To explore the effect of direct association between a photosensitizer and DNA a well know DNA-binding dye, DAPI, was converted into a photosensitizer. Br-DAPI - unlike native DAPI - upon irradiation produces ROS. We demonstrate that the ROS are only effective in inducing dsDNA breaks when Br-DAPI is bound to DNA. In cancer cells (A549) Br-DAPI causes rapid light dependent cell death. This work supports the design of photosensitizers which bind with high affinity to the DNA of target cells for potentially more effective PDT.


Assuntos
Bromo/química , DNA/química , Indóis/química , Fármacos Fotossensibilizantes/química , Células A549 , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , Corantes Fluorescentes/química , Humanos , Luz , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Estudo de Prova de Conceito , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo
12.
Chemistry ; 25(55): 12795-12800, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376182

RESUMO

The controllable ion transport in the photoreceptors of rod cells is essentially important for the light detection and information transduction in visual systems. Herein, inspired by the photochromism-regulated ion transport in rod cells with stacking structure, layered ion channels have been developed with a visual photochromic function induced by the alternate irradiation with visible and UV light. The layered structure is formed by stacking spiropyran-modified montmorillonite 2D nanosheets on the surface of an alumina nanoporous membrane. The visual photochromism resulting from the photoisomerization of spiropyran chromophores reversibly regulates the ion transport through layered ion channels. Furthermore, the cooperation of photochromism and pH value achieves multiple switchable states of layered ion channels for the controllable ion transport mimicking the biological process of the visual cycle. The ion transport properties of these states are explained quantitatively by a theoretical calculation based on the Poisson and Nernst-Plank (PNP) equations.


Assuntos
Benzopiranos/química , Indóis/química , Canais Iônicos/química , Transporte de Íons/fisiologia , Nitrocompostos/química , Células Fotorreceptoras Retinianas Cones/química , Células Fotorreceptoras Retinianas Cones/metabolismo , Raios Ultravioleta
13.
Eur J Med Chem ; 182: 111589, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425906

RESUMO

A series of aryl-substituted indole and indoline derivatives were discovered as novel RORγt agonists by a scaffold-based hybridization of the reported RORγt agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent RORγt agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC50 of 20.8 ±â€¯1.5 nM, the (S)-enantiomer (EC50 = 16.1 ±â€¯4.5 nM) of which was 17 times more potent than the (R) counterpart (EC50 = 286 ±â€¯30.4 nM) in RORγ dual FRET assay. The cell-based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC50 of 247 ±â€¯33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t1/2 = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds. Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of RORγt agonist for cancer immunotherapy.


Assuntos
Descoberta de Drogas , Indóis/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/síntese química , Indóis/química , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 182: 111568, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419778

RESUMO

The human protozoan parasites Leishmania donovani and L. infantum are the causative agents of visceral leishmaniasis, as such, responsible for approximately 30,000 deaths annually. The available chemotherapeutic treatments are reduced to a few drugs whose effectiveness is limited by rising drug resistance/therapeutic failure, and noxious side-effects. Therefore, new therapeutic hits are needed. Compounds displaying the imidazo[2,1-a]isoindole skeleton have shown antichagasic, anti-HIV, antimalarial and anorectic activities. Here, we report the leishmanicidal activity of thirty one imidazo[2,1-a]isoindol-5-ol derivatives on promastigotes and intracellular amastigotes of L. donovani. Eight out of thirty one assayed compounds showed EC50 values ranging between 1 and 2 µM with selectivity indexes from 29 to 69 on infected THP-1 cells. Six compounds were selected for further elucidation of their leishmanicidal mechanism. In this regard, compound 29, the imidazoisoindolol with the highest activity on intracellular amastigotes, induced an early decrease of intracellular ATP levels, as well as mitochondrial depolarization, together with a partial plasma membrane destructuration, as assessed by transmission electron microscopy. Consequently, the inhibition of the energy metabolism of Leishmania plays an important role in the leishmanicidal mechanism of this compound, even when other additional targets cannot be ruled out. In all, the results supported the inclusion of the imidazoisoindole scaffold for the development of new leishmanicidal drugs.


Assuntos
Antiprotozoários/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , Leishmania donovani/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Imidazóis/síntese química , Imidazóis/química , Indóis/síntese química , Indóis/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 182: 111588, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421630

RESUMO

Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal ''lid'' segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds.


Assuntos
Antineoplásicos/farmacologia , Proteínas Intrinsicamente Desordenadas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cianetos/síntese química , Cianetos/química , Cianetos/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Formiatos/síntese química , Formiatos/química , Formiatos/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo
16.
J Photochem Photobiol B ; 198: 111582, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31442827

RESUMO

Poly(lactide-co-glycolide) (PLGA) has been used for the encapsulation of phthalocyanine motived by its biocompatibility and biodegradability. Many studies have already been done to evaluate the influence of parameters used in the PLGA nanoparticle synthesis but without the evaluation of the combinatory interaction between these parameters on the nanoparticulate properties. Ga(III)-phthalocyanine (GaPc) was encapsulated into the PEGlated PLGA-nanoparticles and the individual and combinatory effects of the emulsification time, the method used for the nanoparticle synthesis and the temperature of the aqueous phase was evaluated on the size, entrapment efficiency, efficacy of nanoparticle recovery, residual PVA and zeta potential value using a 23 factorial design (FD). Mathematical models were adjustable to the data and evolutionary operations were performed to optimize the nanoparticle size. The ability of the optimized nanoparticle to decrease the viability of the Hepa-1C1C7 cell and the blood red cell was also evaluated. The FD disclosed the emulsification-diffusion method decreased the residual PVA and the size of PLGA-PEG nanoparticle, but also decreased the entrapment efficiency of GaPc, the zeta potential absolute value and the recovery efficacy of nanoparticles. The combinatory effect between the method used in the nanoparticle preparation and the temperature of aqueous phase influenced four of the five evaluated properties. The viability of Hepa-1C1C7 cells was reduced until 13× when the cells were irradiated in the presence of encapsulated GaPc while it was decreased until 4.7× when the experiment was carried out with the free GaPc. The encapsulated GaPc was also more efficient to cause the haemolysis of the RBC than it was the free GaPc. The optimization of the nanoparticles synthesis increased the efficiency of the GaPc to oxidize the evaluated cells.


Assuntos
Gálio/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Indóis/química , Nanopartículas/toxicidade , Tamanho da Partícula , Temperatura Ambiente
19.
Biophys Chem ; 253: 106228, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31349136

RESUMO

The spectral and the photophysical properties of phthalocyanines have made these dyes attractive for applications in photodynamic therapy of cancer. One important known issue of these compounds is their tendency to aggregate in aqueous media, which decreases their fluorescence, triplet, and singlet oxygen quantum yields. We report on the use of apomyoglobin as a carrier for zinc phthalocyanine (ZnPc) to overcome solubility limitations of the dye. We show that the protein is able to bind ZnPc in monomeric form, preserving its photophysics. Confocal fluorescence imaging of PC3 and HeLa cells, treated with the complex between ZnPc and apomyoglobin, demonstrates that the photosensitizer is uptaken quickly by cells. Illumination of treated cells strongly decreases viability, as demonstrated by live/dead fluorescence assay.


Assuntos
Apoproteínas/química , Indóis/farmacologia , Mioglobina/química , Neoplasias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/química , Neoplasias/patologia , Imagem Óptica , Compostos Organometálicos/química , Células PC-3 , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Propriedades de Superfície , Células Tumorais Cultivadas
20.
J Photochem Photobiol B ; 197: 111554, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326843

RESUMO

Bovine mastitis is an endemic disease of dairy cattle that is considered to be one of the most frequent and costly diseases in veterinary medicine. An increase in the incidence of disease results in the increased use of antibiotics, which in turn increases the potential of bacterial resistance. This study aimed to investigate the effectiveness of antimicrobial photodynamic therapy (aPDT) in the treatment of bovine mastitis, as an alternative to systemic antibiotics. To identify the key factors affecting photoinactivation efficacy, realistic experiments in view of the end-use were conducted in milk samples using two different photosensitizers: methylene blue (MB) and silicon (IV) phthalocyanine derivative (SiPc). We explored the effects of divalent ions and fat content on the aPDT outcome and determined influence of different proteins on aPDT efficacy. Levels of bacterial sensitivity to PSs varied depending on the type of bacteria (Gram-positive vs. Gram-negative) and light exposure time. Critical interrelated factors affecting aPDT in milk were identified and an efficient combination of treatment conditions that can lead to a full photodynamic inactivation of bacteria was determined.


Assuntos
Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Leite/microbiologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Bovinos , Feminino , Indóis/química , Indóis/farmacologia , Indóis/uso terapêutico , Luz , Mastite Bovina/tratamento farmacológico , Mastite Bovina/microbiologia , Mastite Bovina/patologia , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Proteínas do Leite/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete/metabolismo
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