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1.
J Med Chem ; 64(18): 13373-13393, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34472337

RESUMO

Heme oxygenase-1 (HO-1) promotes heme catabolism exercising cytoprotective roles in normal and cancer cells. Herein, we report the design, synthesis, molecular modeling, and biological evaluation of novel HO-1 inhibitors. Specifically, an amide linker in the central spacer and an imidazole were fixed, and the hydrophobic moiety required by the pharmacophore was largely modified. In many tumors, overexpression of HO-1 correlates with poor prognosis and chemoresistance, suggesting the inhibition of HO-1 as a possible antitumor strategy. Accordingly, compounds 7i and 7l-p emerged for their potency against HO-1 and were investigated for their anticancer activity against prostate (DU145), lung (A549), and glioblastoma (U87MG, A172) cancer cells. The selected compounds showed the best activity toward U87MG cells. Compound 7l was further investigated for its in-cell enzymatic HO-1 activity, expression levels, and effects on cell invasion and vascular endothelial growth factor (VEGF) extracellular release. The obtained data suggest that 7l can reduce cell invasivity acting through modulation of HO-1 expression.

2.
ChemMedChem ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34415107

RESUMO

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the "mutual prodrug" approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.

3.
Molecules ; 26(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361825

RESUMO

Lipid-based nanocarriers (LNs) have made it possible to prolong corneal residence time and improve the ocular bioavailability of ophthalmic drugs. In order to investigate how the LNs interact with the ocular mucosa and reach the posterior eye segment, we have formulated lipid nanocarriers that were designed to bear a traceable fluorescent probe in the present work. The chosen fluorescent probe was obtained by a conjugation reaction between fluoresceinamine and the solid lipid excipient stearic acid, forming a chemically synthesized adduct (ODAF, N-(3',6'-dihydroxy-3-oxospiro [isobenzofuran-1(3H),9'-[9H] xanthen]-5-yl)-octadecanamide). The novel formulation (LN-ODAF) has been formulated and characterized in terms of its technological parameters (polydispersity index, mean particle size and zeta potential), while an in vivo study was carried out to assess the ability of LN-ODAF to diffuse through different ocular compartments. LN-ODAF were in nanometric range (112.7 nm ± 0.4), showing a good homogeneity and long-term stability. A TEM (transmission electron microscopy) study corroborated these results of characterization. In vivo results pointed out that after ocular instillation, LN ODAF were concentrated in the cornea (two hours), while at a longer time (from the second hour to the eighth hour), the fluorescent signals extended gradually towards the back of the eye. From the results obtained, LN-ODAF demonstrated a potential use of lipid-based nanoparticles as efficient carriers of an active pharmaceutical ingredient (API) involved in the management of retinal diseases.


Assuntos
Córnea/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas/administração & dosagem , Segmento Posterior do Olho/metabolismo , Compostos de Espiro/administração & dosagem , Animais , Córnea/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Segmento Posterior do Olho/efeitos dos fármacos , Coelhos , Compostos de Espiro/química
4.
Viruses ; 13(8)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34452524

RESUMO

Sand flies transmit Leishmania infantum, which is responsible for causing leishmaniasis, as well as many phleboviruses, including the human pathogenic Toscana virus. We screened sand flies collected from a single site between 2017 and 2020 for the presence of both phleboviruses and Leishmania. The sand flies were sampled with attractive carbon dioxide traps and CDC light traps between May and October. We collected more than 50,000 sand flies; 2826 were identified at the species level as Phlebotomus perfiliewi (98%) or Phlebotomus perniciosus (2%). A total of 16,789 sand flies were tested in 355 pools, and phleboviruses were found in 61 pools (6 Toscana virus positive pools, 2 Corfou virus positive pools, 42 Fermo virus positive pools, and 7 Ponticelli virus positive pools, and 4 unidentified phlebovirus positive pools). Leishmania was found in 75 pools and both microorganisms were detected in 16 pools. We isolated nine phleboviruses from another 2960 sand flies (five Ponticelli viruses and for Fermo viruses), not tested for Leishmania; the complete genome of a Fermo virus isolate was sequenced. The simultaneous detection in space and time of the Fermo virus and L. infantum is evidence that supports the co-circulation of both microorganisms in the same location and partial overlap of their cycles. A detailed characterization of the epidemiology of these microorganisms will support measures to limit their transmission.

5.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202711

RESUMO

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1-4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Heme Oxigenase-1/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias , Receptores sigma/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Receptores sigma/metabolismo
6.
J Med Chem ; 64(12): 7926-7962, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34076441

RESUMO

Since their discovery as distinct receptor proteins, the specific physiopathological role of sigma receptors (σRs) has been deeply investigated. It has been reported that these proteins, classified into two subtypes indicated as σ1 and σ2, might play a pivotal role in cancer growth, cell proliferation, and tumor aggressiveness. As a result, the development of selective σR ligands with potential antitumor properties attracted significant attention as an emerging theme in cancer research. This perspective deals with the recent advances of σR ligands as novel cytotoxic agents, covering articles published between 2010 and 2020. An up-to-date description of the medicinal chemistry of selective σ1R and σ2R ligands with antiproliferative and cytotoxic activities has been provided, including major pharmacophore models and comprehensive structure-activity relationships for each main class of σR ligands.


Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
7.
Int Urol Nephrol ; 53(9): 1773-1783, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34114152

RESUMO

PURPOSE: The primary objective of this study was to evaluate the testicular stiffness by ultrasound shear wave elastography (SWE) both in men with oligo-astheno-teratozospermia (OAT) and in control group. The secondary objective was to identify a possible correlation between semen quality with testicular stiffness. METHODS: This was a prospective case-control study. We divided the sample in two groups; Group A (case group) included men with OAT, and Group B (control group) men with normal sperm parameters. All participants had at last two semen analysis in the past 180 days (at last 90 days apart), using performed ultrasound and SWE elastography. RESULTS: We analyzed 100 participants, 50 patients in Group A and 50 controls in Group B. There were statistically significant differences in term of testicular volume and testicular stiffness between two groups. Men with OAT had the testicular stiffness value higher than the controls in both sides (left testicular stiffness 21.4 ± 5.4 kPa vs 9.9 ± 1.6 kPa, p < 0.0001; right testicular stiffness 22.9 ± 4.8 kPa vs 9.5 ± 2.4 kPa, p < 0.0001). Men with abnormal semen parameters showed an inverse correlation between the mean value of testicular stiffness and total sperm count (22.15 ± 3.38 kPa, r = - 0.387, p = 0.005), sperm concentration (22.15 ± 3.38 kPa, r = - 0.244, p = 0.04), and progressive motility (22.15 ± 3.38 kPa, r = - 0.336, p = 0.01), while the correlation was not evident in controls group. CONCLUSION: SWE is able to differentiate between testicles with spermatogenic changes from a healthy testicle. For this reason, it could be used to evaluate, in a non-invasive way, the tissue alterations of the organ.

8.
ACS Chem Neurosci ; 12(11): 2003-2012, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34019387

RESUMO

σ-1 receptors (σ1R) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σ1R and selectivity over the σ-2 receptor (σ2R). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one (15) showed the highest σ1R receptor affinity (Ki σ1 = 1.6 nM) among the series with a significant improvement of the σ1R selectivity (Ki σ2/Ki σ1 = 886) compared to the lead compound 8 (Ki σ2/Ki σ1 = 432). Compound 15 was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3-60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound 15 demonstrated no significant effects in a rotarod assay, suggesting that this σ1R antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σ1R antagonists as potential therapeutics for chronic pain.


Assuntos
Receptores sigma , Analgésicos/farmacologia , Animais , Hiperalgesia/tratamento farmacológico , Ligantes , Camundongos , Relação Estrutura-Atividade
9.
Int J Esthet Dent ; 16(2): 202-215, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33969975

RESUMO

The patient's facial characteristics play an essential role in achieving a customized smile restoration with appropriate individualized tooth shapes. By initially studying the patient's face, an approach can be determined to plan new individual tooth shapes to achieve a satisfactory outcome. The dental esthetic rehabilitation taking the facial proportion into account involves a complex planning process. To successfully realize such a project, several factors must be evaluated when designing the restoration, including dental alignment, crown dimension, color, occlusion, and facial proportions. Understanding all the anatomical parameters is essential to creating a harmonious esthetic restoration. The facial type of a patient is not only defined by facial symmetry, asymmetry or anthropology but also by an awareness of things through the physical senses (perception); the way things seem, look or feel (impression); and the perceiver's personal interpretation of esthetic excellence and attractiveness (beauty). Other aspects of the face that can be defined for the purposes of the restoration project include strong, dynamic, delicate, and calm.1,2 Nowadays, many patients seek a more attractive appearance. There are several techniques available to perform esthetically pleasing restorations. Ongoing research is being conducted in this area, for instance, the concept known as oral facial harmony.3,4 Dentists have been conducting orofacial analyses for decades, a process that involves applying mathematical rules and geometry principles to create parallel or perpendicular lines on a patient's face. The aim is to achieve harmony rather than symmetry in the redefinition of the smile, because people's faces are naturally asymmetric. The idea, then, is to create a balanced harmonious smile in relation to the patient's face, which is more important than trying to create a mathematically perfect symmetrical smile.5.


Assuntos
Estética Dentária , Dente , Beleza , Face , Humanos , Sorriso
10.
J Comput Aided Mol Des ; 35(3): 297-314, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33615401

RESUMO

Leishmaniasis is an infectious disease caused by parasites of the genus Leishmania and transmitted by the bite of a sand fly. To date, most available drugs for treatment are toxic and beyond the economic means of those affected by the disease. Protein disulfide isomerase (PDI) is a chaperone protein that plays a major role in the folding of newly synthesized proteins, specifically assisting in disulfide bond formation, breakage, or rearrangement in all non-native proteins. In previous work, we demonstrated that Leishmania major PDI (LmPDI) has an essential role in pathogen virulence. Furthermore, inhibition of LmPDI further blocked parasite infection in macrophages. In this study, we utilized a computer-aided approach to design a series of LmPDI inhibitors. Fragment-based virtual screening allowed for the understanding of the inhibitors' modes of action on LmPDI active sites. The generated compounds obtained after multiple rounds of virtual screening were synthesized and significantly inhibited target LmPDI reductase activity and were shown to decrease in vitro parasite growth in human monocyte-derived macrophages. This novel cheminformatics and synthetic approach led to the identification of a new series of compounds that might be optimized into novel drugs, likely more specific and less toxic for the treatment of leishmaniasis.

12.
Bioorg Chem ; 104: 104310, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33010625

RESUMO

The enzymatic family of heme oxygenase (HO) is accountable for heme breakdown. Among the two isoforms characterized to date, HO-2 is poorly investigated due to the lack of potent HO-2 chemical modulators and the greater attentiveness towards HO-1 isoform. In the present paper, we report the rational design and synthesis of HO-2 inhibitors achieved by modulating the volume of known HO-1 inhibitors. The inhibition preference has been moved from HO-1 to HO-2 by merely increasing the volume of the substituent in the western region of the inhibitors. Docking studies demonstrated that new derivatives soak differently in the two binding pockets, probably due to the presence of a Tyr187 residue in HO-2. These findings could be useful for the design of new selective HO-2 compounds.


Assuntos
Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Nitrilas/farmacologia , Algoritmos , Animais , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Heme Oxigenase (Desciclizante)/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Ratos , Baço/enzimologia , Relação Estrutura-Atividade
13.
Sensors (Basel) ; 20(12)2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32570725

RESUMO

In a recent paper, the authors discussed the feasibility study of an innovative technique based on the directionality of Cherenkov light produced in a transparent material to improve the signal to noise ratio in muon imaging applications. In particular, the method was proposed to help in the correct identification of incoming muons direction. After the first study by means of Monte Carlo simulations with Geant4, the first reduced scale prototype of such a detector was built and tested at the Department of Physics and Astronomy "E. Majorana" of the University of Catania (Italy). The characterization technique is based on muon tracking by means of the prototype in coincidence with two scintillating tiles. The results of this preliminary test confirm the validity of the technique and stressed the importance to enhance the Cherenkov photons production to get a signal well distinguishable with respect to sensors and electronic noise.

14.
Molecules ; 25(8)2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32316541

RESUMO

The synthesis of seventeen new 1,3-diaryl-5-oxo-proline derivatives as endothelin receptor (ETR) ligands is described. The structural configuration of the new molecules was determined by analyzing selected signals in proton NMR spectra. In vitro binding assays of the human ETA and ETB receptors allowed us to identify compound 31h as a selective ETAR ligand. The molecular docking of the selected compounds and the ETA antagonist atrasentan in the ETAR homology model provided insight into the structural elements required for the affinity and the selectivity of the ETAR subtype.


Assuntos
Técnicas de Química Sintética , Dipeptídeos/química , Modelos Moleculares , Receptor de Endotelina A/química , Sítios de Ligação , Dipeptídeos/síntese química , Ligantes , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Receptor de Endotelina A/metabolismo , Análise Espectral
15.
Int J Esthet Dent ; 15(1): 92-106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994538

RESUMO

OBJECTIVE: The aim of this study was to create mathematical modeling to generate statistical models that reliably and quickly identify facial type while smiling. This analysis enables the creation of a digital design for the prosthetic restoration of the anterior teeth. MATERIALS AND METHODS: The study involved the computer analysis of 91 facial images. Through mathematical modeling, digital facial maps were generated consisting of 27 landmark points and 12 basic lines determining the facial type. Four main facial types were defined for the purposes of this study: strong, dynamic, delicate, and calm. Selected data were recorded in a database and analyzed using IBM SPSS Modeler software. RESULTS: A varying number of combinations characterize the face; 61.5% of people have the features of two facial types, and 38.5% of three facial types. The overall analysis of the data for both genders shows the most accurate model for predicting facial type by digital facial map is the created algorithm C5.1 (classification tree), with a general prediction accuracy of 84.3%. CONCLUSION: Dental Anatomical Combinations with Rebel Simplicity systems is a constructive way to ensure harmonious unity between the teeth and the facial type. Digital facial maps provide reliable and fast identification of the facial type while smiling. This analysis enables the creation of a digital design for the prosthetic restoration of the anterior teeth.


Assuntos
Sorriso , Dente , Estética Dentária , Face , Feminino , Masculino
16.
Eur J Med Chem ; 183: 111703, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550661

RESUMO

Heme oxygenase (HO) enzymes are involved in heme catabolism and several physiological functions. Among the different HO isoforms, HO-2 stands out for its neuroprotective properties and modulatory activity in male reproduction. However, unlike the HO-1 ligands, the potential therapeutic applications of HO-2 inhibitors/activators have not been extensively explored yet. Moreover, the physiological role of HO-2 is still unclear, mostly due to the lack of highly selective HO-2 chemical probes. To boost the interest on this intriguing target, the present review updates the knowledge on the structure-activity relationships of HO-2 inhibitors and activators, as well as their potential therapeutic applications. To the best of our knowledge, among HO-2 inhibitors, clemizole derivatives are the most selective HO-2 inhibitors reported so far (IC50 HO-1 >100 µM, IC50 HO-2 = 3.4 µM), while the HO-2 nonselective inhibitors described herein possess IC50 HO-2 values ≤ 10 µM. Furthermore, the development of HO-2 activators, such as menadione analogues, helped to understand the critical moieties required for HO-2 activation. Recent advances in the potential therapeutic applications of HO-2 inhibitors/activators cover the fields of neurodegenerative, cardiovascular, inflammatory, and reproductive diseases further stimulating the interest towards this target.


Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/metabolismo , Vitamina K 3/farmacologia , Animais , Benzimidazóis/química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Vitamina K 3/química
17.
Eur J Med Chem ; 183: 111690, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526973

RESUMO

The present paper describes the synthesis and the binding properties for the serotonergic 5-HT7 and 5-HT1A receptors of three new series (A-C) of (benzo)thienopyrimidinone derivatives. All series exhibit a basic moiety at the 2-position of the heterocyclic scaffold such as N,N-dialkylaminoalkylthio chain in series A and phenylpiperazine, benzylpiperazine, or benzylpiperidine alkyl chain in series B and C. Compounds endowed with the best binding properties at 5-HT7R belong to the B and C types. In particular, derivatives B2 and C1 (RSC4) exhibit notable affinity for 5-HT7R (Ki = 9.08 and 0.85 nM, respectively) and selectivity over the 5-HT1AR (254- and 48-fold, respectively). The structure-affinity relationships for these three new classes of 5-HT7R ligands are discussed and, in order to rationalize and deeply investigate the observed results, molecular modeling studies were performed. In particular, the binding poses of the synthesized compounds were studied by docking them in the two receptor proteins suitably built by homology modeling. The calculated binding energies resulted in an excellent agreement with the experimental measured Ki, further validating the quality of the models.


Assuntos
Pirimidinas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
18.
Future Med Chem ; 11(13): 1523-1536, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31469335

RESUMO

Aim: Dimethyl fumarate (DMF) analogs were synthesized to obtain inducers of HO-1 and antifibrotic agents. Methods: HO-1 expression levels were measured on lung fibroblasts (MRC5). NMR and docking studies were performed. Heme oxygenase activity, gene levels and protein expression have been measured for the most active compound 1a. Collagen production by fibroblast after exposure to TGF-ß was measured. Results: Compound 1a showed to be a strong HO-1 inducer. Its activity seems to be mediated by activation of nuclear factor erythroid 2 related factor 2 (Nrf2). TGF-ß-induced collagen production was significantly decreased on MRC5, pretreated with DMF or 1a. DMF and 1a have a high potential for treatment of lung fibrotic injuries.


Assuntos
Fumarato de Dimetilo/farmacologia , Fibrinolíticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibrose/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Pulmão/efeitos dos fármacos , Fumarato de Dimetilo/síntese química , Fumarato de Dimetilo/química , Fibrinolíticos/síntese química , Fibrinolíticos/química , Fibroblastos/metabolismo , Humanos , Pulmão/metabolismo , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo
19.
Eur J Med Chem ; 174: 226-235, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042618

RESUMO

A new set of 5-chlorobenzoxazole- and 5-chlorobenzothiazole-based derivatives containing the azepane ring as a basic moiety was designed, synthesized and evaluated through binding assays to measure their affinity and selectivity towards σ1 and σ2 receptors. Compounds 19, 22 and 24, with a four units spacer between the bicyclic scaffold and the azepane ring, showed nanomolar affinity towards both receptor subtype and the best Ki values (Ki σ1 = 1.27, 2.30, and 0.78 and Ki σ2 = 7.9, 3.8, and 7.61 nM, respectively). Evaluation of cytotoxic and apoptotic effects in MCF-7 human cancer cells was useful to assess σ2 receptor activity, while an in vivo mice model of inflammatory pain allowed to analyze σ1 receptor pharmacological properties. In vitro and in vivo results suggested that compound 19 is a σ1/σ2 agonist, compound 24 a σ1 antagonist/σ2 agonist, whereas compound 22 might act as σ1 antagonist/σ2 partial agonist. Due to their pharmacological profile, a potential therapeutic application in cancer of aforesaid novel σ1/σ2 receptor ligands, especially 22 and 24, is proposed.


Assuntos
Analgésicos/uso terapêutico , Benzotiazóis/uso terapêutico , Benzoxazóis/uso terapêutico , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Humanos , Ligantes , Células MCF-7 , Camundongos , Estrutura Molecular
20.
Int J Mol Sci ; 20(10)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137785

RESUMO

High levels of heme oxygenase (HO)-1 have been frequently reported in different human cancers, playing a major role in drug resistance and regulation of cancer cell redox homeostasis. Metformin (MET), a drug widely used for type 2 diabetes, has recently gained interest for treating several cancers. Recent studies indicated that the anti-proliferative effects of metformin in cancer cells are highly dependent on glucose concentration. The present work was directed to determine whether use of a specific inhibitor of HO-1 activity, alone or in combination with metformin, affected metastatic prostate cancer cell viability under different concentrations of glucose. MTT assay and the xCELLigence system were used to evaluate cell viability and cell proliferation in DU145 human prostate cancer cells. Cell apoptosis and reactive oxygen species were analyzed by flow cytometry. The activity of HO-1 was inhibited using a selective imidazole-based inhibitor; genes associated with antioxidant systems and cell death were evaluated by qRT-PCR. Our study demonstrates that metformin suppressed prostate cancer growth in vitro and increased oxidative stress. Disrupting the antioxidant HO-1 activity, especially under low glucose concentration, could be an attractive approach to potentiate metformin antineoplastic effects and could provide a biochemical basis for developing HO-1-targeting drugs against solid tumors.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Metformina/farmacologia , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Espécies Reativas de Oxigênio/metabolismo
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