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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.
J Med Chem ; 64(15): 11597-11613, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34319100

RESUMO

The potential anticancer effect of fluoroquinolone antibiotics has been recently unveiled and related to their ability to interfere with DNA topoisomerase II. We herein envisioned the design and synthesis of novel Ciprofloxacin and Norfloxacin nitric oxide (NO) photo-donor hybrids to explore the potential synergistic antitumor effect exerted by the fluoroquinolone scaffold and NO eventually produced upon light irradiation. Anticancer activity, evaluated on a panel of tumor cell lines, showed encouraging results with IC50 values in the low micromolar range. Some compounds displayed intense antiproliferative activity on triple-negative and doxorubicin-resistant breast cancer cell lines, paving the way for their potential use to treat aggressive, refractory and multidrug-resistant breast cancer. No significant additive effect was observed on PC3 and DU145 cells following NO release. Conversely, antimicrobial photodynamic experiments on both Gram-negative and Gram-positive microorganisms displayed a significant killing rate in Staphylococcus aureus, accounting for their potential effectiveness as selective antimicrobial photosensitizers.

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 Enzyme Inhib Med Chem ; 36(1): 1378-1386, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34167427

RESUMO

In this work, the first mutual prodrug of 5-fluorouracil and heme oxygenase1 inhibitor (5-FU/HO-1 hybrid) has been designed, synthesised, and evaluated for its in vitro chemical and enzymatic hydrolysis stability. Predicted in silico physicochemical properties of the newly synthesised hybrid (3) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation towards human prostate (DU145) and lung (A549) cancer cell lines demonstrated that 3 exerted a similar effect on cell viability to that produced by the reference drug 5-FU. Among the two tested cancer cell lines, the A549 cells were more susceptible for 3. Of note, hybrid 3 also had a significantly lower cytotoxic effect on healthy human lung epithelial cells (BEAS-2B) than 5-FU. Altogether our results served as an initial proof-of-concept to develop 5-FU/HO-1 mutual prodrugs as potential novel anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Fluoruracila/química , Heme Oxigenase-1/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Pró-Fármacos/síntese química , Ratos , Ratos Sprague-Dawley , Suínos
7.
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
8.
Antioxidants (Basel) ; 10(6)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067436

RESUMO

Glucose induces corneal epithelial dysfunctions characterized by delayed wound repair. Nuclear erythroid 2-related factor 2 (Nrf2) mediates cell protection mechanisms even through the Heme oxygenase-1 (HO-1) up-regulation. Here, we synthesized new HO-1 inducers by modifying dimethyl fumarate (DMF) and used docking studies to select VP13/126 as a promising compound with the best binding energy to Kelch-like ECH-associated protein 1 (keap1), which is the the regulator of Nrf2 nuclear translocation. We verified if VP13/126 protects SIRC cells from hyperglycemia compared to DMF. SIRC were cultured in normal (5 mM) or high glucose (25 mM, HG) in presence of DMF (1-25 µM) or VP13/126 (0.1-5 µM) with or without ERK1/2 inhibitor PD98059 (15 µM). VP13/126 was more effective than DMF in the prevention of HG-induced reduction of cell viability and proliferation. Reduction of wound closure induced by HG was similarly counteracted by 1 µM VP13/126 and 10 µM DMF. VP13/126 strongly increased phospho/total ERK1/2 and restored HO-1 protein in HG-treated SIRC; these effects are completely counteracted by PD98059. Moreover, high-content screening analysis showed a higher rate of Nrf2 nuclear translocation induced by VP13/126 than DMF in HG-stimulated SIRC. These data indicate that VP13/126 exerts remarkable pro-survival properties in HG-stimulated SIRC, promoting the Nrf2/HO-1 axis.

9.
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
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.

11.
Antioxidants (Basel) ; 10(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374280

RESUMO

Resveratrol (RSV) is well known for its many beneficial activities, but its unfavorable physicochemical properties impair its effectiveness after systemic and topical administration; thus, several strategies have been investigated to improve RSV efficacy. With this aim, in this work, we synthesized a novel RSV triester with trolox, an analogue of vitamin E with strong antioxidant activity. The new RSV derivative (RSVTR) was assayed in vitro to evaluate its antioxidant and anti-glycation activity compared to RSV. RSVTR chemical stability was assessed at pH 2.0, 6.8, and 7.2 and different storage temperatures (5 °C, 22 °C, and 37 °C). An influence of pH stronger than that of temperature on RSVTR half-life values was pointed out, and RSVTR greatest stability was observed at pH 7.2 and 5 °C. RSVTR showed a lower antioxidant ability compared to RSV (determined by the oxygen radical absorbance capacity assay) while its anti-glycation activity (evaluated using the Maillard reaction) was significantly greater than that of RSV. The improved ability to inhibit the glycation process was attributed to a better interaction of RSVTR with albumin owing to its increased topological polar surface area value and H-bond acceptor number compared to RSV. Therefore, RSVTR could be regarded as a promising anti-glycation agent worthy of further investigations.

12.
J Pharm Biomed Anal ; 191: 113610, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32971495

RESUMO

Sigma-1 receptors are found throughout the nervous system and play a role in regulating nociception. They are highly expressed in nerve injury, making them a potential target for the treatment of neuropathic pain. Although sigma-1 receptor antagonists have been shown to have anti-nociceptive and anti-allodynic effects, improved selectivity of these ligands is needed to further investigate their potential to treat neuropathic pain. MCI-92 is a novel, selective sigma-1 receptor ligand developed to address this need. A sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of MCI-92 in mouse plasma and brain homogenate. A structural analog of the analyte, MCI-147, was used as the internal standard (IS). The chromatographic separation was achieved on an Acquity UPLC BEH C18 column using a mobile phase consisting of water acidified with 0.1 % v/v formic acid and acetonitrile with gradient elution over 3.2 min. The method was linear over a concentration range of 1-200 ng/mL. Multiple reaction monitoring in the positive ionization mode was used for the mass spectrometric quantitation using m/z transitions 369.2 > 126.0 for MCI-92 and 448.9 > 350.1 for the IS. The method was successfully applied to the analysis of plasma and brain samples obtained in the course of oral and intravenous pharmacokinetic studies in CD-1 mice. MCI-92 showed a high volume of distribution (11.3 ± 0.6 L/kg) and rapid clearance (6.1 ± 0.8 L/h/kg) from systemic circulation. The concentration of the MCI-92 was higher in the brain than in plasma throughout all terminal time points, indicating high blood-to-brain partitioning and slow brain clearance.


Assuntos
Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Ligantes , Camundongos , Ratos , Ratos Sprague-Dawley , Receptores sigma , Reprodutibilidade dos Testes
13.
AAPS J ; 22(5): 94, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32691179

RESUMO

The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca2+ regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10 min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.


Assuntos
Analgésicos/farmacologia , Receptores sigma/agonistas , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos , Ratos Sprague-Dawley
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 Mol Sci ; 21(6)2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32168943

RESUMO

In this paper, a novel series of imidazole-based heme oxygenase-1 (HO-1) inhibitors is reported. These compounds were obtained by modifications of previously described high potent and selective arylethanolimidazoles. In particular, simplification of the central linker and repositioning of the hydrophobic portion were carried out. Results indicate that a hydroxyl group in the central region is crucial for the potency as well as the spatial distribution of the hydrophobic portion. Docking studies revealed a similar interaction of the classical HO-1 inhibitors with the active site of the protein. The most potent and selective compound (5a) was tested for its potential cytotoxic activity against hormone-sensitive and hormone-resistant breast cancer cell lines (MCF-7 and MDA-MB-231).


Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/enzimologia , Heme Oxigenase-1/antagonistas & inibidores , Imidazóis/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular
16.
Bioorg Chem ; 99: 103777, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32222619

RESUMO

Heme oxygenase-1 (HO-1) has been recognized as extensively involved in the development and aggravation of cancer, cell propagation and at in the mechanism of chemoresistance development. Low micromolar HO-1 inhibitors selective towards HO-2 has been recently reported, wherein the azole core and the hydrophobic residues are linked through a phenylethanolic spacer bearing a chiral center. Since less information are known about the stereoselective requirements for HO-1 inhibition, here we report the enantiomeric resolution of 1-(biphenyl-3-yl)-2-(1H-imidazol-1-yl)ethanol (1) and 1-[4-[(4-bromobenzyl)oxy]phenyl]-2-(1H-imidazol-1-yl)ethanol (2), two among the most potent and selective HO-1 inhibitors known thus far when tested as racemates. The absolute configuration was established for 1 by a combination of experimental and in silico derived electronic circular dichroism spectra, while docking approaches were useful in the case of compound 2. Biological evaluation of pure enantiomers highlighted higher HO-1 inhibitory activity of (R)-enantiomers. Docking studies demonstrated the importance of hydrogen bond interaction, more pronounced for the (R)-enantiomers, with a consensus water molecule within the binding pocket. The present study demonstrates that differences in three-dimensional structure amongst compounds 1 and 2 enantiomers affect significantly the selectivity of these HO-1 inhibitors.


Assuntos
Azóis/farmacologia , Inibidores Enzimáticos/farmacologia , Álcool Feniletílico/farmacologia , Animais , Azóis/química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Álcool Feniletílico/química , Ratos , Ratos Sprague-Dawley , Baço/enzimologia , Estereoisomerismo , Relação Estrutura-Atividade
17.
Daru ; 28(1): 387-401, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32060737

RESUMO

Pain represents an unpleasant sensation linked to actual or potential tissue damage. In the early phase, the sensation of pain is caused due to direct stimulation of the sensory nerve fibers. On the other hand, the pain in the late phase is attributed to inflammatory mediators. Current medicines used to treat inflammation and pain are effective; however, they cause severe side effects, such as ulcer, anemia, osteoporosis, and endocrine disruption. Increased attention is recently being focused on the examination of the analgesic potential of phytoconstituents, such as glycosides of traditional medicinal plants, because they often have suitable biological activities with fewer side effects as compared to synthetic drugs. The purpose of this article is to review for the first time the current state of knowledge on the use of glycosides from medicinal plants to induce analgesia and anti-inflammatory effect. Various databases and search engines, including PubMed, ScienceDirect, Scopus, Web of Science and Google Scholar, were used to search and collect relevant studies on glycosides with antinociceptive activities. The results led to the identification of several glycosides that exhibited marked inhibition of various pain mediators based on different well-established assays. Additionally, these glycosides were found to induce most of the analgesic effects through cyclooxygenase and lipoxygenase pathways. These findings can be useful to identify new candidates which can be clinically developed as analgesics with better bioavailability and reduced side effects. Graphical abstract Analgesic mechanisms of plant glycosides.


Assuntos
Analgésicos/uso terapêutico , Glicosídeos/uso terapêutico , Dor/tratamento farmacológico , Animais , Humanos , Fitoterapia , Plantas Medicinais
18.
Med Chem Res ; 29(9): 1697-1706, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33584084

RESUMO

In this work we report the structure-activity relationships, binding properties, and metabolic stability studies of a series of benzo[d]thiazol-2(3H)one as sigma receptors (σRs) ligands. Specifically, to improve the metabolic stability of the cyclic amine fragment of our lead compound (SN56), the metabolically unstable azepane ring was replaced with a 1-adatamantamine moiety. Within the synthesized analogs, compound 12 had low nanomolar affinity for the σ1R (K i = 7.2 nM) and moderate preference (61-fold) over the σ2R. In vitro metabolic stability studies showed a slight improvement of the metabolic stability for 7-12, even though an extensive metabolism in rat liver microsomes is being observed. Furthermore, metabolic soft spot identification of 12 suggested that the N-methyl group of the adamantyl moiety is a major site of metabolism.

19.
Fitoterapia ; 139: 104370, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629872

RESUMO

Ginseng is an ancient herb, belonging to Asian traditional medicine, that has been considered as a restorative to enhance vitality for centuries. It has been demonstrated that the antioxidant action of ginseng may be mediated through activation of different cellular signaling pathways involving the heme oxygenase (HO) system. Several compounds derived from ginseng have been studied for their potential role in brain, heart and liver protection, and the Nrf2 pathway seems to be the most affected by these natural molecules to exert this effect. Ginseng is also popularly used in cancer patients therapy for the demonstrated capability to defend tissues from chemotherapy-induced damage. Reported results suggest that the effect of ginseng is primarily associated with ROS scavenging, mainly exerted through the activation of Nrf2 pathway, and the consequent induction of HO-1 levels. This review aims to discuss the connection between the antioxidant properties of ginseng and the activation of the HO system, as well as to outline novel therapeutic applications of this medicinal plant to human health.


Assuntos
Antioxidantes/farmacologia , Ginsenosídeos/farmacologia , Heme Oxigenase-1/fisiologia , Panax/química , Antineoplásicos Fitogênicos/farmacologia , Cardiotônicos/farmacologia , Humanos , Fator 2 Relacionado a NF-E2/fisiologia , Fármacos Neuroprotetores/farmacologia , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Transdução de Sinais
20.
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
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