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1.
Artigo em Inglês | MEDLINE | ID: mdl-31973020

RESUMO

Nickel is a transition element extensively distributed in the environment, air, water, and soil. It may derive from natural sources and anthropogenic activity. Although nickel is ubiquitous in the environment, its functional role as a trace element for animals and human beings has not been yet recognized. Environmental pollution from nickel may be due to industry, the use of liquid and solid fuels, as well as municipal and industrial waste. Nickel contact can cause a variety of side effects on human health, such as allergy, cardiovascular and kidney diseases, lung fibrosis, lung and nasal cancer. Although the molecular mechanisms of nickel-induced toxicity are not yet clear, mitochondrial dysfunctions and oxidative stress are thought to have a primary and crucial role in the toxicity of this metal. Recently, researchers, trying to characterize the capability of nickel to induce cancer, have found out that epigenetic alterations induced by nickel exposure can perturb the genome. The purpose of this review is to describe the chemical features of nickel in human beings and the mechanisms of its toxicity. Furthermore, the attention is focused on strategies to remove nickel from the environment, such as phytoremediation and phytomining.

2.
ChemMedChem ; 15(1): 136-154, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31743599

RESUMO

Pyridoclax is considered a promising anticancer drug, acting as a protein-protein interaction disruptor, with potential applications in the treatment of ovarian, lung, and mesothelioma cancers. Eighteen sensibly selected structural analogues of Pyridoclax were synthesized, and their physicochemical properties were systematically assessed and analyzed. Moreover, considering that drug-membrane interactions play an essential role in understanding the mode of action of a given drug and its eventual toxic effects, membrane models were used to investigate such interactions in bulk (liposomes) and at the air-water interface. The measured experimental data on all original oligopyridines allowed the assessment of relative differences in terms of physicochemical properties, which could be determinant for their druggability, and hence for drug development.

3.
Bioorg Med Chem Lett ; 30(3): 126905, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874823

RESUMO

Cancer is a complex issue and, even though the prevention basics and therapy have been implemented, it is still the second leading death cause worldwide. With the hope to discover new powerful and safer molecules to fight cancer, many researchers focused their attention on metal-based compounds, starting from the most famous and successfully employed anticancer drug, i.e. cisplatin. The current article aims to report the most recent discoveries about the use of gold, silver and copper complexes as antitumor agents, highlighting their influences on important enzymes, namely human topoisomerases. The latter are fundamental for the cell life and, if overexpressed, strongly implicated in cancer onset and progression. The identification of lead complexes targeting human topoisomerases and gifted with the appropriate chemical and pharmacological properties represents a fecund starting point to obtain new and more effective anticancer molecules.

4.
Eur J Med Chem ; 181: 111583, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400710

RESUMO

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4-9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4).


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Desenho de Drogas , Feminino , Humanos , Simulação de Acoplamento Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Inibidores da Topoisomerase I/química , Moduladores de Tubulina/química
5.
Food Funct ; 10(7): 4280-4290, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31264668

RESUMO

The present study aimed to determine the chemical composition, antioxidant effects and antitumor properties of a methanol extract of Anchusa azurea Mill. (Boraginaceae) aerial parts against four tumour cell lines (MCF-7, MDA-MB-231, RKO, and R2C). The antioxidant effects were assessed by using ß-carotene bleaching, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing ability power (FRAP) tests. HPLC analyses revealed chlorogenic acid, catechin, caffeic acid, and astragalin as the most abundant compounds. Interesting results were obtained in the ß-carotene bleaching test with IC50 values of 7.6 and 27.5 µg mL-1 after 30 and 60 min of incubation, respectively. Furthermore, the A. azurea extract protects 3T3-L1 mouse cells from oxidative stress induced by menadione and exhibits good antitumor activity, with very low toxicity. Our data indicate that the antitumor properties are due to the ability to induce programmed cancer cell death through caspase 3/7 and 9 activation and interference with the cytoskeleton dynamics.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Boraginaceae/química , Citoesqueleto/efeitos dos fármacos , Componentes Aéreos da Planta/química , Extratos Vegetais/farmacologia , Animais , Antioxidantes/farmacologia , Benzotiazóis , Compostos de Bifenilo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Picratos , Espécies Reativas de Oxigênio , Ácidos Sulfônicos
7.
J Nutr Biochem ; 69: 151-162, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31096072

RESUMO

Recently the attention of the scientific community has focused on the ability of polyphenols to counteract adverse epigenetic regulation involved in the development of complex conditions such as obesity. The aim of this study was to investigate the epigenetic mechanisms underlying the anti-adiposity effect of Quercetin (3,3',4',5,7-pentahydroxyflavone) and of one of its derivatives, Q2 in which the OH groups have been replaced by acetyl groups. In 3 T3-L1 preadipocytes, Quercetin and Q2 treatment induce chromatin remodeling and histone modifications at the 5' regulatory region of the two main adipogenic genes, c/EBPα and PPARγ. Chromatin immunoprecipitation assays revealed a concomitant increase of histone H3 di-methylation at Lys9, a typical mark of repressed gene promoters, and a decrease of histone H3 di-methylation at Lys 4, a mark of active transcription. At the same time, both compounds inhibited histone demethylase LSD1 recruitment to the 5' region of c/EBPα and PPARγ genes, a necessary step for adipogenesis. The final effect is a significant reduction in c/EBPα and PPARγ gene expression and attenuated adipogenesis. Q2 supplementation in rats reduced the gain in body weight and in white adipose tissue, as well as the increase in adipocyte size determined by high fat diet. Moreover, Q2 improved dyslipidemia, glucose tolerance and decreased the hepatic lipid accumulation by activating the expression of beta-oxidation related genes. Our data suggest that Q2, as well as Quercetin, has the potential to revert the unfavorable epigenomic profiles associated with obesity onset. This opens the possibility to use these compounds in targeted prevention strategies against obesity.

8.
Int J Mol Sci ; 20(6)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893846

RESUMO

Resveratrol (3,5,4'-trihydroxystilbene; RSV) is a natural nonflavonoid polyphenol present in many species of plants, particularly in grapes, blueberries, and peanuts. Several in vitro and in vivo studies have shown that in addition to antioxidant, anti-inflammatory, cardioprotective and neuroprotective actions, it exhibits antitumor properties. In mammalian models, RSV is extensively metabolized and rapidly eliminated and therefore it shows a poor bioavailability, in spite it of its lipophilic nature. During the past decade, in order to improve RSV low aqueous solubility, absorption, membrane transport, and its poor bioavailability, various methodological approaches and different synthetic derivatives have been developed. In this review, we will describe the strategies used to improve pharmacokinetic characteristics and then beneficial effects of RSV. These methodological approaches include RSV nanoencapsulation in lipid nanocarriers or liposomes, nanoemulsions, micelles, insertion into polymeric particles, solid dispersions, and nanocrystals. Moreover, the biological results obtained on several synthetic derivatives containing different substituents, such as methoxylic, hydroxylic groups, or halogens on the RSV aromatic rings, will be described. Results reported in the literature are encouraging but require additional in vivo studies, to support clinical applications.


Assuntos
Resveratrol/administração & dosagem , Resveratrol/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Halogênios/química , Humanos , Lipossomos , Resveratrol/química , Resveratrol/farmacocinética
9.
Food Funct ; 9(12): 6618-6631, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30511058

RESUMO

Pomegranate peels are the major by-products of the processing of pomegranate juice. Scientific research studies have shown that pomegranate peels are an extraordinary source of bioactive compounds, most of which can be converted into value added products. From this point of view, the present study was carried out with the aim of providing a solid basis for the use of whole pomegranate peels (Akko variety) as a source of nutraceutical compounds, such as ß-glucans. Moreover, acetone (S1) and methanolic (S2) extracts, obtained in the preliminary stage of the ß-glucan isolation procedure, have been tested for their antioxidant and antitumor activities. The total phenolic content and phenolic profile of S1 and S2 were determined. S1 and S2 exhibited a significant DPPH scavenging activity, with an IC50 value for S1 1.5-fold lower than that for the standard Trolox. Both S1 and S2 extracts possess in vitro ROS scavenging activity toward 3T3-L1 murine fibroblasts and Hek-293 human embryonic kidney epithelial cells and antiproliferative activity towards human breast MCF-7 and uterine HeLa cancer cells.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/isolamento & purificação , Lythraceae/química , Extratos Vegetais/isolamento & purificação , Resíduos/análise , beta-Glucanas/isolamento & purificação , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Frutas/química , Humanos , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , beta-Glucanas/química
10.
ChemMedChem ; 13(24): 2635-2643, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30347518

RESUMO

Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic stage of the disease. Treatment regimens are generally tailored for each patient's particular situation. However, chemotherapeutic agents are the leading cause of serious drug-related adverse effects; moreover, drug resistance often occurs. In this study, we designed and synthesized a new series of N-alkylcarbazoles derived from ellipticine, an alkaloid with a carbazole skeleton initially used in the treatment of metastatic breast cancer and later dismissed because of poor aqueous solubility and severe side effects. After evaluating the binding modes of our class of newly synthesized compounds with human topoisomerase II (hTopo II), we performed hTopo II decatenation assays, identifying compound 4 f (2-(4-((3-chloro-9H-carbazol-9-yl)pentyl)piperazin-1-yl)-N,N,N-trimethylethanammonium iodide) as a good inhibitor. Moreover, 4 f and 4 g (2-(4-((3-chloro-9H-carbazol-9-yl)hexyl)piperazin-1-yl)-N,N,N-trimethylethanammonium iodide) showed a good anti-proliferative activity toward breast cancer cells, causing apoptosis by activation of the caspase pathway. Interestingly, the activity of these two compounds on triple-negative MDA-MB-231 cells, which tend to be highly metastatic and aggressive, is strictly connected to the observed inhibition of hTopo II.


Assuntos
Antineoplásicos/química , Carbazóis/química , DNA Topoisomerases Tipo II/metabolismo , Elipticinas/química , Compostos de Amônio Quaternário/química , Inibidores da Topoisomerase II/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama , Carbazóis/síntese química , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Elipticinas/síntese química , Elipticinas/farmacologia , Feminino , Humanos , Simulação de Acoplamento Molecular , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologia
11.
Biometals ; 31(5): 715-735, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30014355

RESUMO

Many evidences indicate that oxidative stress plays a significant role in a variety of human disease states, including neurodegenerative diseases. Iron is an essential metal for almost all living organisms due to its involvement in a large number of iron-containing proteins and enzymes, though it could be also toxic. Actually, free iron excess generates oxidative stress, particularly in brain, where anti-oxidative defences are relatively low. Its accumulation in specific regions is associated with pathogenesis in a variety of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis and Neurodegeneration with Brain Iron Accumulation). Anyway, the extent of toxicity is dictated, in part, by the localization of the iron complex within the cell (cytosolic, lysosomal and mitochondrial), its biochemical form, i.e., ferritin or hemosiderin, as well as the ability of the cell to prevent the generation and propagation of free radical by the wide range of antioxidants and cytoprotective enzymes in the cell. Particularly, ferrous iron can act as a catalyst in the Fenton reaction that potentiates oxygen toxicity by generating a wide range of free radical species, including hydroxyl radicals (·OH). The observation that patients with neurodegenerative diseases show a dramatic increase in their brain iron content, correlated with the production of reactive oxigen species in these areas of the brain, conceivably suggests that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. The aim of this review is to describe the chemical features of iron in human beings and iron induced toxicity in neurodegenerative diseases. Furthermore, the attention is focused on metal chelating drugs therapeutic strategies.


Assuntos
Ferro/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Animais , Humanos , Ferro/efeitos adversos , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/metabolismo , Doenças Neurodegenerativas/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos
12.
J Enzyme Inhib Med Chem ; 33(1): 434-444, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29383954

RESUMO

Synthetic or natural carbazole derivatives constitute an interesting class of heterocycles, which showed several pharmaceutical properties and occupied a promising place as antitumour tools in preclinical studies. They target several cellular key-points, e.g. DNA and Topoisomerases I and II. The most studied representative, i.e. Ellipticine, was introduced in the treatment of metastatic breast cancer. However, because of the onset of dramatic side effects, its use was almost dismissed. Many efforts were made in order to design and synthesise new carbazole derivatives with good activity and reduced side effects. The major goal of the present study was to synthesise a series of new N-thioalkylcarbazole derivatives with anti-proliferative effects. Two compounds, 5a and 5c, possess an interesting anti-proliferative activity against breast and uterine cancer cell lines without affecting non-tumoural cell lines viability. The most active compound (5c) induces cancer cells death triggering the intrinsic apoptotic pathway by inhibition of Topoisomerase II.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Compostos de Sulfidrila/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
13.
Molecules ; 23(2)2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29385738

RESUMO

BACKGROUND: Despite the progress achieved by anti-retroviral drug research in the last decades, the discovery of novel compounds endowed with selective antiviral activity and reduced side effects is still a necessity. At present, the most urgent requirement includes the improvement of HIV (Human Immunodeficiency Virus) prevention and sexual transmission and the development of new drugs to treat the chronic lifelong infection. METHODS: Six chloro-1,4-dimethyl-9H-carbazoles (2a,b-4a,b) have been prepared following opportunely modified known chemical procedures and tested in luciferase and Escherichia coli ß-galactosidase expressing CD4⁺, CXCR4⁺, CCR5⁺ TZM-bl cells. RESULTS AND CONCLUSION: a preliminary biological investigation on the synthesized small series of chloro-1,4-dimethyl-9H-carbazoles has been carried out. Among all tested compounds, a nitro-derivative (3b) showed the most interesting profile representing a suitable lead for the development of novel anti-HIV drugs.


Assuntos
Fármacos Anti-HIV , Carbazóis , Infecções por HIV/prevenção & controle , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Carbazóis/síntese química , Carbazóis/química , Carbazóis/farmacologia , Linhagem Celular , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos
14.
ChemMedChem ; 12(24): 2054-2065, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29120085

RESUMO

Cisplatin and other platinum-based drugs are well-known valid anticancer drugs. However, during chemotherapy, the presence of numerous side effects and the onset of frequent phenomena of resistance has pushed many research groups to devise new metal-based compounds holding improved anticancer properties and fewer undesired effects. Amongst the variety of synthesized compounds, significant antiproliferative effects have been obtained by employing organometallic compounds, particularly those based on silver and gold. With this in mind, we synthesized four compounds, two silver complexes and two gold complexes, with good inhibitory effects on the in vitro proliferation of breast and ovarian cancer-cell models. The antitumor activity of the most active compound, that is, AuL4, was found to be ninefold higher than that of cisplatin, and this compound induced dramatic morphological changes in HeLa cells. AuL4 induced PARP-1 cleavage, caspases 3/7 and 9 activation, mitochondria disruption, cytochrome c release in cancer-cell cytoplasm, and the intracellular production of reactive oxygen species. Thus, AuL4 treatment caused cancer-cell death by the intrinsic apoptotic pathway, whereas no cytotoxic effects were recorded upon treating non-tumor cell lines. The reported outcomes may be an important contribution to the expanding knowledge of medicinal bio-organometallic chemistry and enlarge the available anticancer toolbox, offering improved features, such as higher activity and/or selectivity, and opening the way to new discoveries and applications.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ouro/farmacologia , Metano/análogos & derivados , Espécies Reativas de Oxigênio/metabolismo , Prata/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Humanos , Metano/química , Metano/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Prata/química , Relação Estrutura-Atividade
15.
Future Med Chem ; 9(17): 2011-2028, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29076772

RESUMO

AIM: Quercetin (Q1) is a flavonoid widely present in plants and endowed with several pharmacological properties mostly due to its antioxidant potential. Q1 shows anticancer activity and could be useful in cancer prevention. On the other hand, Q1 is poorly soluble in water and unstable in physiological systems, and its bioavailability is very low. METHODS: A small set of Q1 derivatives (Q2-Q9) has been synthesized following opportunely modified chemical procedures previously reported. Anticancer activity has been evaluated by MTT assay. Human Topoisomerases inhibition has been performed by direct enzymatic assays. Apoptosis has been evaluated by TUNEL assay. ROS production and scavenging activity have been determined by immunofluorescence. RESULTS: The anticancer profile of a small library of Q1 analogues, in which the OH groups were all or partially replaced with hydrophobic functional groups, has been evaluated. Two of the studied compounds demonstrated an interesting cytotoxic profile in two breast cancer models showing the capability to inhibit human Topoisomerases. CONCLUSION: The studied compounds represent suitable leads for the development of innovative anticancer drugs. [Formula: see text].


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases/metabolismo , Quercetina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Inibidores da Topoisomerase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Quercetina/síntese química , Quercetina/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química , Células Tumorais Cultivadas
16.
Curr Opin Pharmacol ; 36: 72-77, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28892800

RESUMO

Diseases related to bacterial infections represent a relevant challenge for public health. Despite the success obtained with the conventional antibiotic therapies, indeed, new drawbacks have been identified. In addition to poor drugs solubility and stability, adverse side effects, and many other factors which together lead to a low patient compliance, the antibiotic resistance and the lack in the development of new antimicrobial agents are the main problems. On the basis of these considerations, the research interest is focused on the exploration of new strategies able to circumvent these drawbacks improving the efficacy of current antibiotics. In this context, nanosized systems, which allow to enhance both the pharmacokinetic profiles and the mechanism of action of drugs, play a key role.


Assuntos
Antibacterianos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Antibacterianos/química , Nanopartículas/química , Polímeros/administração & dosagem , Polímeros/química
18.
Molecules ; 22(4)2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28398240

RESUMO

N-Palmitoyl-ethanolamine (PEA) is an anti-inflammatory component of egg yolk that is usually employed for the prevention of respiratory apparatus virus infection and then frequently used for its efficient anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic, and inflammatory diseases. Nevertheless, data of its use in animal or human therapy are still scarce and further studies are needed. Herein, we report the biological evaluation of a small library of N-palmitoyl-ethanolamine analogues or derivatives, characterized by a protected acid function (either as palmitoyl amides or hexadecyl esters), useful to decrease their hydrolysis rate in vitro and prolong their biological activity. Two of these compounds-namely phenyl-carbamic acid hexadecyl ester (4) and 2-methyl-pentadecanoic acid (4-nitro-phenyl)-amide (5)-have shown good anti-inflammatory and antioxidant properties, without affecting the viability of J774A.1 macrophages. Finally, crystals suitable for X-ray analysis of compound 4 have been obtained, and its solved crystal structure is here reported. Our outcomes may be helpful for a rational drug design based on new PEA analogues/derivatives with improved biological properties.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Etanolaminas/química , Etanolaminas/farmacologia , Modelos Moleculares , Ácidos Palmíticos/química , Ácidos Palmíticos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Molecules ; 22(4)2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28350335

RESUMO

The quest for alternative drugs with respect to the well-known cis-platin and its derivatives, which are still used in more than 50% of the treatment regimens for patients suffering from cancer, is highly needed. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct covalent metal-carbon bond, have recently been found to be promising anticancer drug candidates. A series of new metallocene complexes with scandium, yttrium, and neodymium have been prepared and characterized. Some of these compounds show a very interesting anti-proliferative activity in triple negative breast cancer cell line (MDA.MB231) and the non-hormone sensitive prostate cancer cell line (DU145). Moreover, the interaction of some of them with biological membranes, evaluated using liposomes as bio-membrane mimetic model systems, seems to be relevant. The biological activity of these compounds, particularly those based on yttrium, already effective at low concentrations on both cancer cell lines, should be taken into account with regard to new therapeutic approaches in anticancer therapy.


Assuntos
Antineoplásicos/síntese química , Neodímio/química , Compostos Organometálicos/síntese química , Escândio/química , Ítrio/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia
20.
Drug Deliv ; 24(1): 482-490, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28181828

RESUMO

Sericin is a natural protein that has been used in biomedical and pharmaceutical fields as raw material for polypeptide-based drug delivery systems (DDSs). In this paper, it has been employed as pharmaceutical biopolymer for the production of sunitinib-polypeptide conjugate. The synthesis has been carried out by simple click reaction in water, using the redox couple l-ascorbic acid/hydrogen peroxide as a free radical grafting initiator. The bioconjugate molecular weight (50 kDa < Mw < 75 kDa) was obtained by SDS-PAGE, while the spectroscopic characteristics have been studied in order to reveal the presence of grafted sunitinib. In both FT-IR and UV/Vis spectra, signals corresponding to sunitinib functional groups have been identified. Since sunitinib is an anticancer drug characterized by low bioavailability and low permeability, the bioconjugation aimed at their enhancement. In vitro studies demonstrated that bioavailability has been increased to almost 74%, compared with commercial formulation. Also cell membrane permeability has been augmented in in vitro tests, in which membrane models have been used to determine the lipid membrane/physiological fluid partition coefficient (Kp). The log(Kp) value of the bioconjugate was increased to over 4. This effect resulted in a three-fold decrease of IC50 value against MCF-7 cells.


Assuntos
Antineoplásicos/metabolismo , Permeabilidade da Membrana Celular , Química Click , Portadores de Fármacos , Indóis/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Pirróis/metabolismo , Sericinas/síntese química , Neoplasias do Colo do Útero/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Composição de Medicamentos , Feminino , Células HeLa , Humanos , Indóis/administração & dosagem , Indóis/química , Concentração Inibidora 50 , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirróis/administração & dosagem , Pirróis/química , Solubilidade , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Sunitinibe , Tecnologia Farmacêutica/métodos , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
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