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1.
Molecules ; 26(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361832

RESUMO

In recent times, researchers have aimed for new strategies to combat cancer by the implementation of nanotechnologies in biomedical applications. This work focuses on developing protein-based nanoparticles loaded with a newly synthesized NIR emitting and absorbing phthalocyanine dye, with photodynamic and photothermal properties. More precisely, we synthesized highly reproducible bovine serum albumin-based nanoparticles (75% particle yield) through a two-step protocol and successfully encapsulated the NIR active photosensitizer agent, achieving a good loading efficiency of 91%. Making use of molecular docking simulations, we confirm that the NIR photosensitizer is well protected within the nanoparticles, docked in site I of the albumin molecule. Encouraging results were obtained for our nanoparticles towards biomedical use, thanks to their negatively charged surface (-13.6 ± 0.5 mV) and hydrodynamic diameter (25.06 ± 0.62 nm), favorable for benefitting from the enhanced permeability and retention effect; moreover, the MTT viability assay upholds the good biocompatibility of our NIR active nanoparticles. Finally, upon irradiation with an NIR 785 nm laser, the dual phototherapeutic effect of our NIR fluorescent nanoparticles was highlighted by their excellent light-to-heat conversion performance (photothermal conversion efficiency 20%) and good photothermal and size stability, supporting their further implementation as fluorescent therapeutic agents in biomedical applications.


Assuntos
Indóis/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Soroalbumina Bovina/química , Proliferação de Células , Feminino , Humanos , Indóis/química , Luz , Simulação de Acoplamento Molecular , Nanopartículas/química , Neoplasias Ovarianas/patologia , Fármacos Fotossensibilizantes/química , Espectroscopia de Luz Próxima ao Infravermelho , Células Tumorais Cultivadas
2.
Viruses ; 13(8)2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34452480

RESUMO

We compared the electrostatic properties of the spike proteins (S-proteins) of three coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, and their interactions with photosensitizers (PSs), octacationic octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+) and monocationic methylene blue (MB). We found a major common PS binding site at the connection of the S-protein stalk and head. The molecules of Zn-PcChol8+ and MB also form electrostatic encounter complexes with large area of negative electrostatic potential at the head of the S-protein of SARS-CoV-2, between fusion protein and heptad repeat 1 domain. The top of the SARS-CoV spike head demonstrates a notable area of electrostatic contacts with Zn-PcChol8+ and MB that corresponds to the N-terminal domain. The S-protein protomers of SARS-CoV-2 in "open" and "closed" conformations demonstrate different ability to attract PS molecules. In contrast with Zn-PcChol8+, MB possesses the ability to penetrate inside the pocket formed as a result of SARS-CoV-2 receptor binding domain transition into the "open" state. The existence of binding site for cationic PSs common to the S-proteins of SARS-CoV, SARS-CoV-2, and MERS-CoV creates prospects for the wide use of this type of PSs to combat the spread of coronaviruses.


Assuntos
Indóis/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Compostos Organometálicos/metabolismo , Fármacos Fotossensibilizantes/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sítios de Ligação , Indóis/química , Azul de Metileno/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Compostos Organometálicos/química , Conformação Proteica , Domínios Proteicos , Subunidades Proteicas/química , Vírus da SARS/química , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Eletricidade Estática
3.
J Enzyme Inhib Med Chem ; 36(1): 1810-1828, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338135

RESUMO

Novel quinazolinones conjugated with indole acetamide (4a-c), ibuprofen (7a-e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Hidrazinas/química , Ibuprofeno/química , Indóis/química , Quinazolinonas/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Ibuprofeno/síntese química , Ibuprofeno/farmacologia , Indóis/síntese química , Indóis/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Análise Espectral/métodos
4.
J Enzyme Inhib Med Chem ; 36(1): 1783-1797, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340630

RESUMO

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.


Assuntos
Anidrases Carbônicas/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Isoenzimas/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Anidrases Carbônicas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática , Ativadores de Enzimas/química , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Indóis/química , Isoenzimas/metabolismo , Microglia/citologia , Microglia/efeitos dos fármacos , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Especificidade por Substrato
5.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361566

RESUMO

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.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Citotoxinas , Indóis , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Feminino , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo
6.
Molecules ; 26(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34443327

RESUMO

Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Trifosfato de Adenosina/metabolismo , Antimaláricos/química , Antimaláricos/metabolismo , Sítios de Ligação , Técnicas de Química Sintética , Quinase 3 da Glicogênio Sintase/química , Quinase 3 da Glicogênio Sintase/metabolismo , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Conformação Proteica , Relação Estrutura-Atividade
7.
ACS Appl Mater Interfaces ; 13(33): 39112-39125, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34384220

RESUMO

Autophagy inhibition could hinder the underlying protective mechanisms in the course of tumor treatment. The advances in autophagy inhibition have driven focus on the functionalized nanoplatforms by combining the current treatment paradigms with complementary autophagy inhibition for enhanced efficacy. Furthermore, Ca2+ overload is also a promising adjuvant target for the tumor treatment by augmenting mitochondrial damage. In this view, complementary mitochondrial Ca2+ overload and autophagy inhibition were first demonstrated as a novel strategy suitable for homing in on the shortage of photodynamic therapy (PDT). We constructed biodegradable tumor-targeted inorganic/organic hybrid nanocomposites (DPGC/OI) synchronously encapsulating IR780 and Obatoclax by biomineralization of the nanofilm method, which consists of pH-triggered calcium phosphate (CP), long circulation phospholipid block copolymers 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-poly(ethylene glycol) (PEG)2000-glucose (DPG). In the presence of the hydrophilic PEG chain and glucose transporter 1 (Glut-1) ligands, DPGC would become an effectively tumor-oriented nanoplatform. Subsequently, IR780 as an outstanding photosensitizer could produce increased amounts of toxic reactive oxygen species (ROS) after laser irradiation. Calcium phosphate (CP) as the Ca2+ nanogenerator could generate Ca2+ at low pH to induce mitochondrial Ca2+ overload. The dysfunction of mitochondria could enhance increased amounts of ROS. Based on the premise that autophagy would degrade dysfunctional organelles to sustain metabolism and homeostasis, which might participate in resistance to PDT, Obatoclax as an autophagy inhibitor would hinder the protective mechanism from cancer cells with negligible toxicity. Such an enhanced PDT via mitochondrial Ca2+ overload and autophagy inhibition could be realized by DPGC/OI.


Assuntos
Autofagia/efeitos dos fármacos , Fosfatos de Cálcio/química , Glucose/química , Indóis/química , Nanocompostos/química , Fosfatidiletanolaminas/química , Fármacos Fotossensibilizantes/química , Polietilenoglicóis/química , Animais , Transporte Biológico , Melhoramento Biomédico , Feminino , Humanos , Indóis/metabolismo , Indóis/farmacologia , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Fosfolipídeos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Pirróis/química , Pirróis/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Propriedades de Superfície , Distribuição Tecidual
8.
ACS Appl Mater Interfaces ; 13(33): 39934-39948, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34396771

RESUMO

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Glutationa/química , Indóis/química , Nanopartículas/química , Oxaliplatina/química , Fármacos Fotossensibilizantes/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Glutationa/metabolismo , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/efeitos da radiação , Imunoterapia , Indóis/farmacocinética , Lasers , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Oxaliplatina/farmacocinética , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Polietilenoglicóis/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação
9.
ACS Appl Mater Interfaces ; 13(33): 38969-38978, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34399054

RESUMO

Controlling the microstructure of materials by means of phase separation is a versatile tool for optimizing material properties. Phase separation has been exploited to fabricate intricate microstructures in many fields including cell biology, tissue engineering, optics, and electronics. The aim of this study was to use phase separation to tailor the spatial location of drugs and thereby generate release profiles of drug payload over periods ranging from 1 week to months by exploiting different mechanisms: polymer degradation, polymer diluent dissolution, and control of microstructure. To achieve this, we used drop-on-demand inkjet three-dimensional (3D) printing. We predicted the microstructure resulting from phase separation using high-throughput screening combined with a model based on the Flory-Huggins interaction parameter and were able to show that drug release from 3D-printed objects can be predicted from observations based on single drops of mixtures. We demonstrated for the first time that inkjet 3D printing yields controllable phase separation using picoliter droplets of blended photoreactive oligomers/monomers. This new understanding gives us hierarchical compositional control, from droplet to device, allowing release to be "dialled up" without manipulation of device geometry. We exemplify this approach by fabricating a biodegradable, long-term, multiactive drug delivery subdermal implant ("polyimplant") for combination therapy and personalized treatment of coronary heart disease. This is an important advance for implants that need to be delivered by cannula, where the shape is highly constrained and thus the usual geometrical freedoms associated with 3D printing cannot be easily exploited, which brings a hitherto unseen level of understanding to emergent material properties of 3D printing.


Assuntos
Anti-Hipertensivos/química , Doença das Coronárias/tratamento farmacológico , Portadores de Fármacos/química , Excipientes/química , Indóis/química , Polímeros/química , Anti-Hipertensivos/farmacologia , Dioxanos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Indóis/farmacologia , Metacrilatos/química , Transição de Fase , Poliésteres/química , Impressão Tridimensional , Pirrolidinonas/química , Relação Estrutura-Atividade
10.
Int J Biol Macromol ; 185: 1022-1035, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34197859

RESUMO

Biochemical modification can endow the surface of implants with superior biological activity. Herein, silk fibroin (SF) protein and its anionic derivative peptides (Cs) were covalently immobilized onto a titanium implant surface via a polydopamine layer. The successful conjugation of SF and Cs was revealed by X-ray photoelectron spectroscopy (XPS), field-emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), and contact angle measurements. The addition of Cs prevented the conformational transition of silk fibroin to silk II. The deposition of apatite on its surface was significantly accelerated, and the bioactive composite coating was observed to enhance protein adsorption and cell proliferation. More importantly, it also promoted the osteogenic differentiation of bone marrow stem cells (BMSCs) for the quantitative and qualitative detection of alkaline phosphatase (ALP) and alizarin red (ARS). Overall, the stable performance and enhanced osteogenic property of the composite coating promote an extensive application for clinical titanium-based implants.


Assuntos
Fibroínas/farmacologia , Indóis/química , Células-Tronco Mesenquimais/citologia , Osteogênese/efeitos dos fármacos , Polímeros/química , Titânio/química , Adsorção , Animais , Apatitas/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroínas/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Microscopia de Força Atômica , Oxirredução , Peptídeos/química , Peptídeos/farmacologia , Espectroscopia Fotoeletrônica
11.
Molecules ; 26(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34299385

RESUMO

An efficient and simple protocol for the synthesis of a new class of diverse bis(indolyl)pyridines analogues of the marine alkaloid nortopsentin has been reported. A one-pot four-component condensation of 3-cyanocarbomethylindole, various aldehyde, 3-acetylindole, and ammonium acetate in glacial acetic acid led to the formation of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridine-5-carbonitriles. Additionally, 2,6-bis(1H-indol-3-yl)-4-(benzofuran) pyridine-5-carbonitriles were prepared via a one-pot four-component condensation of 3-cyanocarbomethylindole, various N-substituted-indole-3-aldehydes, 2-acetylbenzofuran, and ammonium acetate. The synthesized compounds were evaluated for their ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 6538 and the Gram-negative strain Escherichia coli ATCC 25922. Some of the new compounds showed a marked selectivity against the Gram-positive and Gram-negative strains. Remarkably, five compounds 4b, 7a, 7c, 7d and 8e demonstrated good antibiofilm formation against S. aureus and E. coli. On the other hand, the release of reducing sugars and proteins from the treated bacterial strains over the untreated strains was considered to explain the disruption effect of the selected compound on the contact cells of S. aureus and E. coli. Out of all studied compounds, the binding energies and binding mode of bis-indole derivatives 7c and 7d were theoretically the best thymidylate kinase, DNA gyrase B and DNA topoisomerase IV subunit B inhibitors.


Assuntos
Alcaloides/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Inibidores Enzimáticos/farmacologia , Indóis/química , Biofilmes/efeitos dos fármacos , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Piridinas/química
12.
Nat Commun ; 12(1): 4310, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262026

RESUMO

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Macrófagos/transplante , Fotoquimioterapia/métodos , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Portadores de Fármacos/química , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Indóis/administração & dosagem , Indóis/química , Indóis/farmacologia , Raios Infravermelhos , Macrófagos/química , Nanomedicina , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxaliplatina/administração & dosagem , Oxaliplatina/química , Oxaliplatina/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia
13.
Molecules ; 26(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206893

RESUMO

PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) to be significantly more active than (R)-PF74 (IC50 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = -73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = -55.8 kcal/mol) in agreement with experimental observations.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/metabolismo , Capsídeo/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Fenilalanina/análogos & derivados , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Capsídeo/química , Cromatografia Líquida de Alta Pressão , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Estereoisomerismo
14.
Molecules ; 26(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299651

RESUMO

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.


Assuntos
Inibidores Enzimáticos , Ácido Glicirretínico , Indóis , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Pirazóis , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/química , Humanos , Indóis/síntese química , Indóis/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
15.
J Enzyme Inhib Med Chem ; 36(1): 1665-1678, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34309457

RESUMO

Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC50 = 80.3 vs. 9.97 and 9.57 µg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading to reduced enzyme activity. In addition, OA indole derivatives showed feasible skin permeability in a slightly acidic environment (pH = 6.5) and 6c exerted skin protective effect by reducing cellular reactive oxygen species in human skin keratinocytes. Findings from the current study support that OA indole derivatives are potential cosmeceuticals with anti-hyaluronidase activity.


Assuntos
Inibidores Enzimáticos/farmacologia , Hialuronoglucosaminidase/antagonistas & inibidores , Indóis/farmacologia , Ácido Oleanólico/farmacologia , Pele/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hialuronoglucosaminidase/metabolismo , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Permeabilidade/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Pele/metabolismo , Relação Estrutura-Atividade
16.
J Photochem Photobiol B ; 222: 112256, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34330080

RESUMO

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.


Assuntos
Cloreto de Alumínio/farmacologia , Fibroblastos/efeitos dos fármacos , Indóis/farmacologia , Luz , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Cloreto de Alumínio/química , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Colágeno/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Humanos , Indóis/química , Metaloproteinase 9 da Matriz/metabolismo , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo
17.
Photochem Photobiol Sci ; 20(7): 939-953, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34255302

RESUMO

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.


Assuntos
Anti-Infecciosos/farmacologia , Indóis/farmacologia , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Tensoativos/farmacologia , Anti-Infecciosos/química , Candida albicans/efeitos dos fármacos , Cátions/química , Cátions/farmacologia , Escherichia coli/efeitos dos fármacos , Indóis/química , Testes de Sensibilidade Microbiana , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/química , Staphylococcus aureus/efeitos dos fármacos , Tensoativos/química
18.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201422

RESUMO

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.


Assuntos
Acetileno/química , Antivirais/química , Antivirais/síntese química , Indóis/química , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , SARS-CoV-2/enzimologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Calicreínas/antagonistas & inibidores , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos
19.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204914

RESUMO

In this paper, we report the development of the novel self-assembling systems based on oppositely charged Pillar[5]arenes and surfactants for encapsulation of diagnostic dye DAPI. For this purpose, the aggregation behavior of synthesized macrocycles and surfactants in the presence of Pillar[5]arenes functionalized by carboxy and ammonium terminal groups was studied. It has been demonstrated that by varying the molar ratio in Pillar[5]arene-surfactant systems, it is possible to obtain various types of supramolecular systems: host-guest complexes at equimolar ratio of Pillar[5]arene-surfactant and interpolyelectrolyte complexes (IPECs) are self-assembled materials formed in aqueous medium by two oppositely charged polyelectrolytes (macrocycle and surfactant micelles). It has been suggested that interaction of Pillar[5]arenes with surfactants is predominantly driven by cooperative electrostatic interactions. Synthesized stoichiometric and non-stoichiometric IPECs specifically interact with DAPI. UV-vis, luminescent spectroscopy and molecular docking data show the structural feature of dye-loaded IPEC and key role of the electrostatic, π-π-stacking, cation-π interactions in their formation. Such a strategy for the design of supramolecular Pillar[5]arene-surfactant systems will lead to a synergistic interaction of the two components and will allow specific interaction with the third component (drug or fluorescent tag), which will certainly be in demand in pharmaceuticals and biomedical diagnostics.


Assuntos
Calixarenos/química , Indóis/química , Polieletrólitos/química , Tensoativos/química , Compostos de Amônio/química , Cátions/química , Micelas , Simulação de Acoplamento Molecular , Eletricidade Estática , Água/química
20.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201401

RESUMO

The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known compounds is one of the proposed strategies. The objective of this study was to perform in vitro experimental tests of already identified lead compounds in our previous in silico drug repurposing study, which had been conducted on the known Drugbank database using a seven-step procedure which includes machine learning and molecular docking. This study identifies siramesine as a novel antifungal agent. This novel indication was confirmed through in vitro testing using several yeast species and one mold. The results showed susceptibility of Candida species to siramesine with MIC at concentration 12.5 µg/mL, whereas other candidates had no antifungal activity. Siramesine was also effective against in vitro biofilm formation and already formed biofilm was reduced following 24 h treatment with a MBEC range of 50-62.5 µg/mL. Siramesine is involved in modulation of ergosterol biosynthesis in vitro, which indicates it is a potential target for its antifungal activity. This implicates the possibility of siramesine repurposing, especially since there are already published data about nontoxicity. Following our in vitro results, we provide additional in depth in silico analysis of siramesine and compounds structurally similar to siramesine, providing an extended lead set for further preclinical and clinical investigation, which is needed to clearly define molecular targets and to elucidate its in vivo effectiveness as well.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Indóis/química , Indóis/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Simulação por Computador , Reposicionamento de Medicamentos/métodos , Ergosterol/metabolismo , Aprendizado de Máquina , Simulação de Acoplamento Molecular/métodos
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