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1.
J Nat Prod ; 86(1): 166-175, 2023 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-36542806

RESUMO

A fluorescent labeling protocol for hydroxylated natural compounds with promising antitumor properties has been used to synthesize, in yields of 72-86%, 12 derivatives having fluorescent properties and biological activity. The reagent used for the synthesis of these fluorescent derivatives was 7-nitrobenzo-2-oxa-1,3-diazole chloride (NBD-Cl). The linkers employed to bind the NBD-Cl reagent to the natural compounds were ω-amino acids (Aa) of different chain lengths. The natural triterpene compounds chosen were oleanolic and maslinic acid, as their corresponding 28-benzylated derivatives. Thus, 12 NBD-Aa-triterpene conjugates have been studied for their optical fluorescence properties and their biological activities against cell proliferation in three cancer cell lines (B16-F10, HT-29, and HepG2), compared with three nontumor cell lines (HPF, IEC-18, and WRL68) from different tissues. The results of the fluorescence study have shown that the best fluorescent labels are those in which the ω-amino acid chain is shorter, and the carboxylic group is not benzylated. Analysis by confocal microscopy showed that these compounds were rapidly incorporated into cells in all three cancer cell lines, with these same derivatives showing the highest toxicity against the cancer cell lines tested. Then, the fluorescent labeling of these NBD-Aa-triterpene conjugates enabled their uptake and subcellular distribution to be followed in order to probe in detail their biological properties at the cellular and molecular level.


Assuntos
Triterpenos , Humanos , Transporte Biológico , Corantes Fluorescentes/farmacologia , Corantes Fluorescentes/química , Células HT29 , Triterpenos/farmacologia , Triterpenos/química
2.
Molecules ; 28(17)2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37687037

RESUMO

Pterolobirin H (3), a cassane diterpene isolated from the roots of Pterolobium macropterum, exhibits important anti-inflammatory and anticancer properties. However, its relatively complex tetracyclic structure makes it difficult to obtain by chemical synthesis, thus limiting the studies of its biological activities. Therefore, we present here a short route to obtain a rational simplification of pterolobirin H (3) and some intermediates. The anti-inflammatory activity of these compounds was assayed in LPS-stimulated RAW 264.7 macrophages. All compounds showed potent inhibition of NO production, with percentages between 54 to 100% at sub-cytotoxic concentrations. The highest anti-inflammatory effect was shown for compounds 15 and 16. The simplified analog 16 revealed potential NO inhibition properties, being 2.34 higher than that of natural cassane pterolobirin H (3). On the other hand, hydroxyphenol 15 was also demonstrated to be the strongest NO inhibitor in RAW 264.7 macrophages (IC50 NO = 0.62 ± 0.21 µg/mL), with an IC50NO value 28.3 times lower than that of pterolobirin H (3). Moreover, the anticancer potential of these compounds was evaluated in three cancer cell lines: HT29 colon cancer cells, Hep-G2 hepatoma cells, and B16-F10 murine melanoma cells. Intermediate 15 was the most active against all the selected tumor cell lines. Compound 15 revealed the highest cytotoxic effect with the lowest IC50 value (IC50 = 2.45 ± 0.29 µg/mL in HT29 cells) and displayed an important apoptotic effect through an extrinsic pathway, as evidenced in the flow cytometry analysis. Furthermore, the Hoechst staining assay showed that analog 15 triggered morphological changes, including nuclear fragmentation and chromatin condensation, in treated HT29 cells. Finally, the in silico studies demonstrated that cassane analogs exhibit promising binding affinities and docking performance with iNOS and caspase 8, which confirms the obtained experimental results.


Assuntos
Anti-Inflamatórios , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Bioensaio , Linhagem Celular Tumoral
3.
J Nat Prod ; 85(10): 2372-2384, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36215157

RESUMO

A new strategy for the semisynthesis of the aromatic cassane-type diterpene taepeenin F (6) is reported. The introduction of the methyl group at C-14, characteristic of the target compound, was achieved via dienone 13, easily prepared from abietic acid (10), the major compound in renewable rosin. Biological assays of selected compounds are reported. The antiproliferative activity against HT29, B16-F10, and HepG2 tumor cell lines has been investigated. Salicylaldehyde 21 was the most active compound (IC50 = 7.72 µM). Products 16 and 21 displayed apoptotic effects in B16-F10 cells, with total apoptosis rates of 46 and 38.4%, respectively. This apoptotic process involves a significant arrest of the B16-F10 cell cycle, blocking the G0/G1 phase. Dienone 16 did not cause any loss of the mitochondrial membrane potential (MMP), while salicylaldehyde 21 caused a partial loss of the MMP. The anti-inflammatory activity of the selected compounds was investigated with the LPS-stimulated RAW 264.7 macrophages. All compounds showed potent NO inhibition, with percentages between 80 and 99% at subcytotoxic concentrations. Dienone 16 inhibited LPS-induced differentiation of RAW 264.7 cells, by increasing the proportion of cells in the S phase. In addition, salicylaldehyde 21 had effects on the cell cycle, recovering the cells from the G0/G1 full arrest produced in response to LPS action.


Assuntos
Antineoplásicos , Diterpenos , Lipopolissacarídeos/farmacologia , Potencial da Membrana Mitocondrial , Apoptose , Linhagem Celular Tumoral , Diterpenos/farmacologia , Anti-Inflamatórios/farmacologia , Proliferação de Células , Antineoplásicos/farmacologia
4.
Molecules ; 27(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36080472

RESUMO

A set of thirteen cassane-type diterpenes was synthesized and an expedient synthetic route was used to evaluate 14-desmethyl analogs of the most active tested cassane. The anti-inflammatory activities of these 13 compounds were evaluated on a lipopolysaccharide (LPS)-activated RAW 264.7 cell line by inhibition of nitric oxide (NO) production, some of them reaching 100% NO inhibition after 72 h of treatment. The greatest anti-inflammatory effect was observed for compounds 16 and 20 with an IC50 NO of 2.98 ± 0.04 µg/mL and 5.71 ± 0.14 µg/mL, respectively. Flow-cytometry analysis was used to determine the cell cycle distribution and showed that the inhibition in NO release was accompanied by a reversion of the differentiation processes. Moreover, the anti-cancer potential of these 13 compounds were evaluated in three tumor cell lines (B16-F10, HT29, and Hep G2). The strongest cytotoxic effect was achieved by salicylaldehyde 20, and pterolobirin G (6), with IC50 values around 3 µg/mL in HT29 cells, with total apoptosis rates 80% at IC80 concentrations, producing a significant cell-cycle arrest in the G0/G1 phase, and a possible activation of the extrinsic apoptotic pathway. Additionally, initial SAR data analysis showed that the methyl group at the C-14 positions of cassane diterpenoids is not always important for their cytotoxic and anti-inflammatory activities.


Assuntos
Antineoplásicos , Caesalpinia , Diterpenos , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Diterpenos/farmacologia , Humanos , Estrutura Molecular , Óxido Nítrico/metabolismo , Polienos/farmacologia
5.
J Nat Prod ; 84(5): 1587-1597, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33956447

RESUMO

A set of 12 maslinic acid-coumarin conjugates was synthesized, with 9 being maslinic acid-diamine-coumarin conjugates at the C-28 carboxylic acid group of triterpene acid and the other three being maslinic acid-coumarin conjugates at C-2/C-3 and/or C-28 of the triterpene skeleton. The cytotoxic effects of these 12 triterpene conjugates were evaluated in three cancer cell lines (B16-F10, HT29, and Hep G2) and compared, respectively, with three nontumor cell lines from the same or similar tissue (HPF, IEC-18, and WRL68). The most potent cytotoxic results were achieved by a conjugate with two molecules of coumarin-3-carboxylic acid coupled through the C-2 and C-3 hydroxy groups of maslinic acid. This conjugate showed submicromolar IC50 values in two of the three cancer cell lines tested (0.6, 1.1, and 0.9 µM), being between 110- and 30-fold more effective than its corresponding precursor. Furthermore, this conjugate (10) showed percentages of cell viability for the three nontumor lines of 90%. Four maslinic acid-coumarin conjugates displayed apoptotic effects in the treated cells, with total apoptosis rates of between 40 and 85%, relative to the control. Almost all the compounds assayed caused cell-cycle arrest in all cancer cell lines, increasing the number of these cells in the G0/G1 phase.


Assuntos
Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos/síntese química , Cumarínicos/síntese química , Células HT29 , Células Hep G2 , Humanos , Melanoma Experimental , Potencial da Membrana Mitocondrial , Camundongos , Estrutura Molecular , Azeite de Oliva , Triterpenos/síntese química
6.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360922

RESUMO

Recent evidence has shown that inflammation can contribute to all tumorigenic states. We have investigated the anti-inflammatory effects of a diamine-PEGylated derivative of oleanolic acid (OADP), in vitro and in vivo with inflammation models. In addition, we have determined the sub-cytotoxic concentrations for anti-inflammatory assays of OADP in RAW 264.7 cells. The inflammatory process began with incubation with lipopolysaccharide (LPS). Nitric oxide production levels were also determined, exceeding 75% inhibition of NO for a concentration of 1 µg/mL of OADP. Cell-cycle analysis showed a reversal of the arrest in the G0/G1 phase in LPS-stimulated RAW 264.7 cells. Furthermore, through Western blot analysis, we have determined the probable molecular mechanism activated by OADP; the inhibition of the expression of cytokines such as TNF-α, IL-1ß, iNOS, and COX-2; and the blocking of p-IκBα production in LPS-stimulated RAW 264.7 cells. Finally, we have analyzed the anti-inflammatory action of OADP in a mouse acute ear edema, in male BL/6J mice treated with OADP and tetradecanoyl phorbol acetate (TPA). Treatment with OADP induced greater suppression of edema and decreased the ear thickness 14% more than diclofenac. The development of new derivatives such as OADP with powerful anti-inflammatory effects could represent an effective therapeutic strategy against inflammation and tumorigenic processes.


Assuntos
Anti-Inflamatórios/farmacologia , Otopatias/tratamento farmacológico , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7
7.
Int J Mol Sci ; 21(9)2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32365648

RESUMO

We have designed and synthesized two novel cobalt coordination compounds using bumetanide (bum) and indomethacin (ind) therapeutic agents. The anti-inflammatory effects of cobalt metal complexes with ind and bum were assayed in lipopolysaccharide stimulated RAW 264.7 macrophages by inhibition of nitric oxide production. Firstly, we determined the cytotoxicity and the anti-inflammatory potential of the cobalt compounds and ind and bum ligands in RAW 264.7 cells. Indomethacin-based metal complex was able to inhibit the NO production up to 35% in a concentration-dependent manner without showing cytotoxicity, showing around 6-37 times more effective than indomethacin. Cell cycle analysis showed that the inhibition of NO production was accompanied by a reversion of the differentiation processes in LPS-stimulated RAW 264.7 cells, due to a decreased of cell percentage in G0/G1 phase, with the corresponding increase in the number of cells in S phase. These two materials have mononuclear structures and show slow relaxation of magnetization. Moreover, both compounds show anti-diabetic activity with low in vitro cell toxicities. The formation of metal complexes with bioactive ligands is a new and promising strategy to find new compounds with high and enhanced biochemical properties and promises to be a field of great interest.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Algoritmos , Animais , Pontos de Checagem do Ciclo Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Imãs , Camundongos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Óxido Nítrico/metabolismo , Células RAW 264.7 , Solubilidade , Relação Estrutura-Atividade
8.
J Nat Prod ; 82(10): 2886-2896, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31617361

RESUMO

Pentacyclic triterpenes, such as oleanolic acid (I), are promising scaffolds for diversification through the use of combinatorial methods to obtain derivatives that improve their biological properties, increasing their bioavailability and enhancing their therapeutic efficacy. The purpose of this study was to evaluate the influence that derivatives of oleanolic acid, conjugated with one or two amino acids and an acyl group, might exert on HIV-1 protease inhibition. The in vitro studies conducted suggested that the presence of a carboxyacyl group generally improves the inhibition of HIV-1 protease, especially when a phthaloyl group is present, with IC50 concentration values below 5 µM. The gain in activity of three 3-phthaloyl derivatives, with sub-micromolar IC50 values, was between 60- and 100-fold more active than oleanolic acid. A molecular docking study has also been performed to elucidate the mode of binding to the protease by these oleanolic acid derivatives. In general, the derivatives that exhibited the highest inhibitory activity of HIV-1 protease also showed the highest binding energies in docking simulations. The overall results suggest that the coupling of one or two amino acids and a phthaloyl group to oleanolic acid improves HIV-1 protease inhibition, implying that these triterpene derivatives may be promising antiviral agents against HIV.


Assuntos
Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Simulação de Acoplamento Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Relação Estrutura-Atividade
9.
Phytochem Anal ; 30(1): 89-94, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30216583

RESUMO

INTRODUCTION: L-Dopa, a key neurotransmitter used to treat neural disorders such as Parkinson's disease, is found in the seeds of the genus Mucuna at a sufficient concentration for possible commercial use. OBJECTIVE: To develop a simple and reliable method to extract L-Dopa from M. pruriens seeds in an aqueous medium and then quantitate this compound using a 1 H qNMR method (internal standard); and also to evaluate the accuracy and reproducibility of this method with an NMR calibration curve. METHODOLOGY: The extraction method of L-Dopa from M. pruriens was optimized. The quantitation with single point quantitative NMR (qNMR) and NMR calibration curve was based on the resonance properties of the main functional groups of the L-Dopa molecule, in particular the signals of the three aromatic protons, which were compared with the signal of an internal standard such as syringic acid. The accuracy (precision and trueness) and reproducibility of both NMR techniques were evaluated. RESULTS: The methods of single point qNMR and NMR calibration curve, applied to the seeds of two M. pruriens varieties, gave very similar L-Dopa contents: 3.0-3.2% and 3.0-3.1%, respectively. CONCLUSION: The statistical analysis confirmed the accuracy and reproducibility of this single point qNMR method (internal standard) for determining L-Dopa, as well as other commercial preparations of this species, without performing an NMR calibration curve.


Assuntos
Levodopa/análise , Mucuna/embriologia , Espectroscopia de Prótons por Ressonância Magnética/métodos , Sementes/química , Ácido Gálico/análogos & derivados , Ácido Gálico/química , Ácido Gálico/normas , Levodopa/isolamento & purificação , Mucuna/classificação , Padrões de Referência , Especificidade da Espécie , Água
10.
J Nat Prod ; 81(9): 2075-2082, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30160961

RESUMO

Several lipophilic ω-hydroxyalkylcarbonate hydroxytyrosol derivatives and also their corresponding dimeric derivatives have been synthesized, coupling the primary hydroxy group of this phenolic compound with several terminal diols of different chain lengths, by the use of a carbonate linker. The trypanocidal activity and cytotoxicity of these ω-hydroxyalkylcarbonate derivatives of hydroxytyrosol and known alkylcarbonate derivatives of hydroxytyrosol were assessed. Three of the hydroxytyrosol alkylcarbonate derivatives were active against Trypanosoma brucei: two with an alkyl chain of average size (0.2 and 0.5 µM) and another with a double bond in the alkyl chain (0.4 µM). These values suggest an increase in activity with respect to hydroxytyrosol (264-, 90-, and 116-fold, respectively). Furthermore, these compounds showed high selectivity indices against MRC-5, a nontumor human cell line (62, 71, and 39, respectively). Some other ω-hydroxyalkylcarbonate and alkylcarbonate derivatives of hydroxytyrosol were also active against T. brucei within a low micromolar range (about 1 µM).


Assuntos
Álcool Feniletílico/análogos & derivados , Tripanossomicidas/síntese química , Linhagem Celular , Humanos , Espectroscopia de Ressonância Magnética , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacos
11.
Dalton Trans ; 53(21): 8988-9000, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38721696

RESUMO

A new family of six complexes based on 5-nitropicolinic acid (5-npic) and transition metals has been obtained: [M(5-npic)2]n (MII = Mn (1) and Cd (2)), [Cu(5-npic)2]n (3), and [M(5-npic)2(H2O)2] (MII = Co (4), Ni (5), and Zn (6)), which display 1D, 2D, and mononuclear structures, respectively, thanks to different coordination modes of 5-npic. After their physicochemical characterization by single-crystal X-ray diffraction (SCXRD), elemental analyses (EA), and spectroscopic techniques, quantum chemical calculations using Time-Dependent Density Functional Theory (TD-DFT) were performed to further study the luminescence properties of compounds 2 and 6. The potential anticancer activity of all complexes was tested against three tumor cell lines, B16-F10, HT29, and HepG2, which are models widely used for studying melanoma, colon cancer, and liver cancer, respectively. The best results were found for compounds 2 and 4 against B16-F10 (IC50 = 26.94 and 45.10 µg mL-1, respectively). In addition, anti-inflammatory studies using RAW 264.7 cells exhibited promising activity for 2, 3, and 6 (IC50 NO = 5.38, 24.10, and 17.63 µg mL-1, respectively). This multidisciplinary study points to complex 2, based on CdII, as a promising anticancer and anti-inflammatory material.


Assuntos
Antineoplásicos , Complexos de Coordenação , Ácidos Picolínicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Camundongos , Animais , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Teoria da Densidade Funcional , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Desenho de Fármacos , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Modelos Moleculares , Células RAW 264.7 , Sobrevivência Celular/efeitos dos fármacos
12.
Biomed Pharmacother ; 163: 114828, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37163783

RESUMO

Maslinic acid (MA) is a natural pentacyclic triterpenoid with inherent antitumor activity which has a very low solubility in water. MA solid lipid nanoparticles (SLNs) were prepared using Poloxamer 407 and Dicarboxylic acid-Poloxamer 407 as surfactants. Both MA SLNs are monodisperse, with sizes around 130 nm, and stable. Curcumin has been encapsulated in both types of nanoparticles without altering their colloidal properties. Moreover, SLNs greatly improve the solubility of MA and Curcumin. The cytotoxicity of MA and SLNs has been evaluated in BxPC3 human pancreatic cancer cells, MCF7 human breast cancer cells, and in a human fibroblast primary cell line. MA shows higher cytotoxic effect in BxPC3 and MCF7 cancer cells than in human primary fibroblasts. Nile Red loaded MA SLNs are quickly uptaken by BxPC3 and MCF7 cells, and show different cytoplasmic distributions depending on the cellular line. The oral or intravenous administration of MA SLNs in mice does not report any toxic effect, and the intravenous administration of fluorescent MA SLNs shows a homogeneous distribution in mice, without site-specific accumulation. Results suggest the great potential of MA SLNs as nanocarriers of anticancer drugs and as promising targeted theranostic nanodevices.


Assuntos
Antineoplásicos , Curcumina , Nanopartículas , Humanos , Camundongos , Animais , Curcumina/farmacologia , Distribuição Tecidual , Lipídeos/química , Poloxâmero , Nanopartículas/química , Portadores de Fármacos/química , Tamanho da Partícula
13.
J Inorg Biochem ; 215: 111308, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33257004

RESUMO

A new family of mononuclear coordination compounds has been synthetized and characterized: [M(3-ind)2(H2O)2] (M = Co (1), Ni (2), Zn (3), Fe (4), Mn (5); 3-ind = indazole-3-carboxylate). These materials are mononuclear coordination compounds that possess strong hydrogen bond interactions. The anti-inflammatory effects of these compounds were assayed in lipopolysaccharide activated RAW 264.7 macrophages by inhibition of NO production. Moreover, the cytotoxicity of the complexes and the ligand in RAW 264.7 cells were determined for the first time. The most significant results were obtained for the compounds 4 and 5 reaching values of NO inhibition close to 80% at 48 h, and above to 90% at 72 h of treatment. The highest inhibitory effects on NO production were showed at the range 7-23 µg/mL for compounds 4 and 5. As a consequence, compounds 4 and 5 could be potential drugs due to the interesting anti-inflammatory properties showed. The anti-cancer potential of these compounds has been also tested against different tumor cell lines. The cytotoxicity of the ligand and of compounds 2 and 3 were assayed in three cell lines: HT29, colon cancer cells, Hep-G2, hepatoma cells and B16-F10 melanoma cells. The best results have been achieved with compound 2 in HepG2 and B16-F10 cell lines, being between 1.5 and 2 times more effective that the ligand in HepG2 cells, and B16-F10 cells. All in all, indazole-3-carboxylic acid is a promising ligand for the formation of coordination compounds with biochemical properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Indazóis/química , Indazóis/farmacologia , Animais , Anti-Inflamatórios/química , Antineoplásicos/química , Cátions Bivalentes/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células HT29 , Células Hep G2 , Humanos , Ligação de Hidrogênio , Íons/química , Ligantes , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7
14.
Biomolecules ; 10(10)2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998255

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell line. The cytotoxicity results showed that HepG2 cell viability was markedly reduced, with a very low 50% of cell growth inhibitory concentration (IC50, 0.14 µg/mL). We then investigated the anti-tumor mechanisms of OADP in HepG2 cells. The flow-cytometry analysis was used to evaluate cell apoptosis, indicating that 74-95% of cells were apoptotic. OADP caused cell cycle arrest in the G0/G1 phase and the loss of the mitochondrial membrane potential (MMP). Western blot analysis was performed to assess the expression levels of key proteins associated with the underlying molecular mechanism. The results showed the clear upregulation of caspase-8, caspase-9, caspase-3, Bak, p21, and p53, accompanied by the downregulation of Bcl-2. Similar results were obtained by the cotreatment with OADP and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Agents such as OADP, which are capable of activating extrinsic and intrinsic apoptotic pathways, may represent potential HCC cancer therapies.


Assuntos
Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Receptores de Morte Celular/metabolismo , Antracenos/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Caspase 3/metabolismo , Diaminas/química , Regulação para Baixo/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Oleanólico/química , Polietilenoglicóis/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Triterpenos/química , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
15.
J Inorg Biochem ; 207: 111051, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32371293

RESUMO

Five new coordination polymers (CPs) constructed of aminopyridine-2-carboxylate (ampy) ligand have been synthesized and fully characterized. Three of them correspond to metal-organic chains built from the coordination of ampy to sodium and lanthanides with formulae [MNa(ampy)4]n (M = terbium (2), erbium (1) and ytterbium (3)) resembling a previously reported dysprosium material which shows anticancer activity. On another level, the reaction of Hampy with cobalt and copper ions ({[CoK(ampy)3(H2O)3](H2O)3}n (4) and [Cu(ampy)2]n (5)) lead to CPs with variable dimensionalities, which gives the opportunity of analyzing the structural properties of this new family. Lanthanide materials display solid state intense photoluminescent emissions in both the visible and near-infrared region and exhibit slow relaxation of magnetization with frequency dependence of the out-of-phase susceptibility. More interestingly, in our search for multifunctional materials, we have carried out antitumor measurements of these compounds. These multidisciplinary studies of metal complexes open up the possibility for further exploring the applications in the fields of metal-based drugs.


Assuntos
Aminopiridinas/química , Antineoplásicos/química , Ácidos Carboxílicos/química , Estruturas Metalorgânicas/química , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Cobalto/química , Complexos de Coordenação/química , Cobre/química , Cristalografia por Raios X/métodos , Células HT29 , Células Hep G2 , Humanos , Elementos da Série dos Lantanídeos/química , Ligantes , Luminescência , Magnetismo , Estruturas Metalorgânicas/farmacologia , Camundongos , Modelos Moleculares , Polímeros/química
16.
J Inorg Biochem ; 208: 111098, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32454248

RESUMO

We report on the formation of two novel multifunctional isomorphous (4,4) square-grid 2D coordination polymers based on 1H-indazole-5-carboxylic acid. To the best of our knowledge, these complexes are the first examples of 2D-coordination polymers constructed with this novel ligand. We have analysed in detail the structural, magnetic and anti-parasitic properties of the resulting materials. In addition, the capability of inhibiting nitric oxide production from macrophage cells has been measured and was used as an indirect measure of the anti-inflammatory response. Finally, the photocatalytic activity was measured with a model pollutant, i.e. vanillic acid (phenolic compound), with the aim of further increasing the functionalities and applicability of the compounds.


Assuntos
Anti-Inflamatórios , Antiprotozoários , Complexos de Coordenação , Citotoxinas , Indazóis , Leishmania/crescimento & desenvolvimento , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Indazóis/química , Indazóis/farmacologia , Camundongos , Células RAW 264.7
17.
Eur J Med Chem ; 148: 325-336, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29471121

RESUMO

A set of 18 amide derivatives of oleanolic or maslinic acid has been semi-synthesised. Twelve were diamine conjugates at C-28 of these triterpenic acids and the other six were PEGylated-diamine derivatives. The cytotoxic effects of these 18 triterpenic derivatives in three cancer-cell lines (B16-F10, HT29, and Hep G2) have been assayed, and have been compared to three non-tumour cell lines of the same or a similar tissue (HPF, IEC-18, and WRL68). The cell viability percentages for the non-tumour HPF line for almost all diamine conjugates of the tested triterpenic acids ranged from 81% to 94%. The best cytotoxic results were achieved with the diamine conjugates of oleanolic or maslinic acid with the shortest and the longest diamine chain (IC50 values from 0.76 µM to 1.76 µM), on the B16-F10 cell line, being between 140- and 20-fold more effective than their corresponding precursors. Four diamine conjugates of these triterpenic acids showed apoptotic effects on treated cells of the B16-F10 line, with total apoptosis rates, relative to control, of between 73% and 90%. The DNA-histogram analysis revealed that all compounds tested produced cell-cycle arrest in B16-F10 cells, increasing the number of these cells in the S phase. All the compounds analysed, except one, did not cause changes in mitochondrial-membrane potential during apoptosis of the B16-F10 cancer cells, suggesting an activation of the extrinsic apoptotic pathway for these compounds.


Assuntos
Antineoplásicos/química , Ácido Oleanólico/química , Triterpenos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diaminas/química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Triterpenos/farmacologia
18.
Fitoterapia ; 120: 25-40, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28552598

RESUMO

A set of PEGylated derivatives of oleanolic and maslinic acids has been semi-synthesised, attaching ethylene glycol, diethylene glycol, triethylene glycol or tetraethylene glycol to the C-28 carboxyl group of these natural triterpenes and some derivatives. Another set of PEGylated derivatives has been semi-synthesised by connecting the same four ethylene glycols to the hydroxyl groups of the A ring of these triterpenic acids, through a carbonate linker, by reaction with trichloromethyl chloroformate. The aqueous solubility of some of these PEGylated derivatives has been compared with that of maslinic acid. The cytotoxic effects of 28 triterpenic PEGylated derivatives in three cancer-cell lines (B16-F10, HT29, and Hep G2) have been assayed. The best results have been achieved with the HT29 cell line, and specifically with the oleanolic acid derivatives having ethylene glycol or tetraethylene glycol attached to the C-28 carboxyl group, which are approximately 27-fold more effective than their natural precursor. Eight PEGylated derivatives have been selected to compare the cytotoxicity results in the HT29 cancer-cell line with those of a non-tumour cell line of the same tissue (IEC-18), four of which were less cytotoxic in the non-tumour cell line. These compounds showed apoptotic effects on treated cells, with percentages of total apoptosis between 20% and 53%, relative to control, at 72h and IC50 concentration, and between 29% to 62%, relative to control, for the same time and IC80 concentration. We have also found that with the treatment of these compounds in HT29 cancer cells, cell-cycle arrest occurred in the G0/G1 phase. Finally, we have also studied changes in mitochondrial membrane potential during apoptosis of HT29 cancer cells, and the results suggest an activation of the extrinsic apoptotic pathway for these compounds.


Assuntos
Antineoplásicos/farmacologia , Ácido Oleanólico/farmacologia , Triterpenos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Oleanólico/química , Polietilenoglicóis/química , Triterpenos/química
19.
Eur J Med Chem ; 118: 64-78, 2016 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-27128174

RESUMO

Several PEGylated derivatives of oleanolic and maslinic acids have been semi-synthesized, attaching one acid-PEG reagent to the hydroxyl group/s at C-2 or C-2/C-3 of the A rings of these natural triterpenes, and also to their corresponding C-28 benzyl derivatives. Several monomeric and dimeric PEGylated compounds have also been produced by linking one diamine-PEG reagent to the carboxyl group at C-28 of the same natural triterpenes and also to their corresponding C-2 or C-2/C-3 acetylated derivatives. The cytotoxic effects of 12 triterpenic PEGylated derivatives in three cancer-cell lines (B16F10, HT29, and Hep G2) have been assayed. The best results have been achieved by the PEGylated-amine derivative of oleanolic acid, with IC50 concentrations between 0.22 and 3.78 µM, being between 28- and 963-fold more effective than its natural precursor. The percentages of apoptosis induction have also been determined for the five PEGylated derivatives with the lowest cytotoxicity data. All five compounds showed apoptotic effects on the treated cells, with a total apoptosis rate of 99% in the B16F10 cells, 80% in the Hep G2 cells, and 51% in the HT29 cells. We have also studied the changes in the mitochondrial membrane potential (MMP) to elucidate the possible mechanism involved in the apoptotic responses (intrinsic or extrinsic). Finally, to verify the results found in the cytometry assays, we have used fluorescence microscopy techniques to determine changes in the cell morphology. These PEGylated derivatives of natural triterpenoids, which can induce apoptosis at very low concentrations in different tumour lines, may represent new effective therapeutic drugs against these diseases.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacologia , Polietilenoglicóis/química , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos
20.
Eur J Med Chem ; 74: 278-301, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24480359

RESUMO

A broad set of potential bioactive conjugate compounds has been semi-synthesized through solution- and solid-phase organic procedures, coupling two natural pentacyclic triterpene acids, oleanolic (OA) and maslinic acids (MA), at the hydroxyl groups of the A-ring of the triterpene skeleton, with 10 different acyl groups. These acyl OA and MA derivatives have been tested for their anti-proliferative (against the b16f10 murine melanoma cancer cells) and antiviral (as inhibitors of the HIV-1-protease) effects. Several derivatives have shown high levels of early and total apoptosis (up to 90%). Most of the compounds that exhibited anti-proliferative effects also generated ROS, probably involving the activation of an intrinsic apoptotic route. The only four compounds that did not cause the release of ROS could be related to the participation of a probable extrinsic activation of the apoptosis mechanism. A great number of these acyl OA and MA derivatives have proved to be potent inhibitors of the HIV-1-protease, the most active inhibitors having IC50 values between 0.31 and 15.6 µM, these values being between 4 and 186 times lower than their non-acylated precursors. The potent activities exhibited in the apoptosis-activation processes and in the inhibition of the HIV-1-protease by some OA and MA acylated derivatives imply that these compounds could be used as new, safe, and effective anticancer and/or antiviral drugs.


Assuntos
Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Resíduos Industriais , Óleos de Plantas , Triterpenos/síntese química , Acilação , Fármacos Anti-HIV/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azeite de Oliva , Espécies Reativas de Oxigênio/metabolismo
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