RESUMO
A series of PdII complexes with bis-(2-pyridylmethyl)glycine as a ligand of formula [PdX(bis-(2-pyridylmethyl)glycine)] where Xâ¯=â¯Cl, Br, I were prepared and the effect of the halogen nature in the antitumor activity of eight tumorigenic and one non-tumorigenic cell line was evaluated. The chloride derivative was further functionalized with a transferrin receptor binding peptide, generating the first PdII based metallopeptide. Its antitumor activity was also evaluated. However, among all the complexes, the chloride and iodine parent compounds showed the lowest GI50 values in the panel evaluated, and lowest GI50 than cisplatin in several cell lines. In contrast, the bromine derivative showed higher values of GI50 than chloride and iodine (around 30 - 50⯵M). The same trend was observed for the bovine serum albumin binding constant with higher values for iodine, chlorine, and bromine in this order. In aqueous solution, the chloride is exchanged by water while the bromine and iodine are not. DNA was evaluated as a target and showed no significative interaction for all the compounds. The results suggest sulfur-rich proteins and not DNA as a target. This report represents the first PdII metallopeptide reported, its evaluation in solution and antitumor activity. This work opens the possibilities for further functionalization of PdII complexes and the importance of the halogen coordination in the design of novel metallodrugs.
Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Halogênios/química , Paládio/química , Peptídeos/química , Peptídeos/farmacologia , Proteínas de Ligação a Transferrina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Células HT29 , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Peptídeos/síntese química , Relação Estrutura-Atividade , Difração de Raios XRESUMO
The search for modulating ligand substitution reaction in gold complexes is essential to find new active metallo compounds for medical applications. In this work, a new linear and hydrosoluble goldI complex with tris-(2-carboxyethylphosphine) (AuTCEP). The two phosphines coordinate linearly to the metal as solved by single crystal X-ray diffraction. Complete spectroscopic characterization is also reported. In vitro growth inhibition (GI50) in a panel of nine tumorigenic and one non-tumorigenic cell lines demonstrated the complex is highly selective to ovarium adenocarcinoma (OVCAR-03) with GI50 of 3.04â¯nmolâ¯mL-1. Moreover, non-differential uptake of AuTCEP was observed between OVCAR-03 (tumor) and HaCaT (non-tumor) two cell lines. Biophysical evaluation with the sulfur-rich biomolecules showed the compound does not interact with two types of zinc fingers, bovine serum albumin, N-acetyl-l-cysteine and also l-histidine, revealing to be inert to ligand substitution reactions with these molecules. However, AuTCEP demonstrated to cleave plasmidial DNA, suggesting DNA as a possible target. No antibacterial activity was observed in the strains evaluated. Besides, it inhibits 15% of the activity of a mixture of serine-ß-lactamase and metallo-ß-lactamase from Bacillus cereus in the enzymatic activity assay, similarly to EDTA. These results suggest AuTCEP is selective to metallo-ß-lactamase but the cell uptake is hindered, and the compound does not reach the periplasmic space of Gram-positive bacteria. The unique inert behavior of AuTCEP is interesting and represent the modulation of the reactivity through coordination chemistry to decrease the toxicity associated with AuI complexes and its lack of specificity, generating very selective compounds with unexpected targets.
Assuntos
Antibacterianos , Antineoplásicos , Complexos de Coordenação , Ouro , Bactérias Gram-Positivas/crescimento & desenvolvimento , Fosfinas , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ouro/química , Ouro/farmacologia , Humanos , Células MCF-7 , Fosfinas/química , Fosfinas/farmacologia , Soroalbumina Bovina/químicaRESUMO
OBJECTIVE: The essential oil from the leaves of Ocimum kilimandscharicum (EOOK), collected in Dourados-MS, was investigated for anticancer, anti-inflammatory and antioxidant activity and chemical composition. MATERIALS AND METHODS: The essential oil was extracted by hydrodistillation, and the chemical composition was performed by gas chromatography-mass spectrometry. The essential oil was evaluated for free radical-scavenging activity using the DPPH assay and was tested in an anticancer assay against ten human cancer cell lines. The response parameter (GI50) was calculated for the cell lines tested. The anti-inflammatory activity was evaluated using carrageenan-induced pleurisy in mice. RESULTS: The chemical composition showed 45 components with a predominance of monoterpenes, such as camphor (51.81%), 1,8 cineole (20.13%) and limonene (11.23%). The EOOK exhibited potent free radical-scavenging activity by the DPPH assay with a GI50 of 8.31 µg/ml. The major constituents, pure camphor (IC50=12.56 µg/ml) and mixture of the limonene: 1, 8 cineole (IC50=23.25 µg/ml) displayed a potent activity. The oral administration of EOOK (at 30 and 100 mg kg(-1)), as well as the pure camphor or a mixture of 1,8 cineole with limonene, significantly inhibited the carrageenan (Cg) induced pleurisy, reducing the migration of total leukocytes in mice by 82 ± 4% (30 mg kg(-1) of EOOK), 95 ± 4% (100 mg kg(-1) of EOOK), 83 ± 9% (camphor) and 80 ± 5% (mixture of 1,8 cineole:limonene 1:1). In vitro cytotoxicity screening against a human ovarian cancer cell line displayed high selectivity and potent anticancer activity with GI50=31.90 mg ml(-1). This work describes the anti-inflammatory, anticancer and antioxidant effects of EOOK for the first time. CONCLUSIONS: The essential oil exhibited marked anti-inflammatory, antioxidant and anticancer effects, an effect that can be attributed the presence of majorital compounds, and the response profiles from chemical composition differed from other oils collected in different locales.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Ocimum/química , Óleos Voláteis/farmacologia , Animais , Cânfora/química , Cânfora/farmacologia , Linhagem Celular Tumoral , Cicloexanóis/química , Cicloexanóis/farmacologia , Cicloexenos/química , Cicloexenos/farmacologia , Eucaliptol , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Limoneno , Camundongos , Monoterpenos/química , Monoterpenos/farmacologia , Óleos Voláteis/química , Folhas de Planta/química , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Terpenos/química , Terpenos/farmacologiaRESUMO
Metabolic surgery for the treatment of type 2 diabetes mellitus (T2DM) in patients not morbidly obese (BMI <35) has been widely studied. Taking into account that â¼12% of pancreas transplants are performed in patients with T2DM, our goal was to evaluate the impact of metabolic surgery on the management of obese patients with T2DM on waiting lists for a pancreas transplant. We performed a Roux-en-Y gastrointestinal bypass in 5 patients with insulin-dependent T2DM who were candidates for pancreas after kidney transplant and with a BMI <35. Three patients became insulin independent by the end of the first year while the other 2 reduced their insulin requirements by 70%. Furthermore, all patients achieved improved control of lipid levels. We concluded that the surgery was effective in controlling blood glucose and lipid metabolism in these obese T2DM kidney transplant recipients. In this population, a pancreas transplant, along with its associated morbidity, may be avoided.
Assuntos
Diabetes Mellitus Tipo 2/cirurgia , Derivação Gástrica , Transplante de Rim , Idoso , Glicemia/análise , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Transplante de Pâncreas , Triglicerídeos/sangueRESUMO
UNLABELLED: Cryptococcosis, a fungal infection that affects both immunocompromised and immunocompetent individuals, contributes to increasing indices of mortality and morbidity. The development of resistance by Cryptococcus spp., the limited number of commercial antifungal drugs and the various side effects of these drugs cause the treatment of cryptococcosis to be a challenge. The in vitro anticryptococcal activity of nine hydroxyaldimines was evaluated against 24 strains of Cryptococcus spp. Antifungal susceptibility was evaluated using a broth microdilution assay following the Clinical and Laboratory Standards Institute guidelines, using fluconazole as a positive control. Parameters such as the minimum inhibitory concentration and the minimum fungicidal concentration (MIC and MFC, respectively) were also determined. Antiproliferative activity on the normal cell line VERO was assessed 48 h post-compound exposure to determine the selectivity index (SI) of the hydroxyaldimines and fluconazole. All hydroxyaldimines were active against Cryptococcus spp. strains. Compounds 3A9 and 3B7 were the most potent against the Cryptococcus gattii and Cryptococcus neoformans strains. Selectivity indices also revealed that 3B10, 3C3, 3D3 and 3D9 are good candidates for in vivo studies. The in vitro anticryptococcal activity of hydroxyaldimines against various strains of C. gattii and C. neoformans indicates the potential of this class of molecules as lead compound for the development of selective and efficient anticryptococcal agents. SIGNIFICANCE AND IMPACT OF THE STUDY: The effectiveness of hydroxyaldimines for inhibition of Cryptococcus spp. growth and their low toxicity against healthy monkey kidney epithelial cells makes them promising lead compounds for the design of new anticryptococcal agents.
Assuntos
Antifúngicos/farmacologia , Cryptococcus gattii/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Iminas/farmacologia , Animais , Chlorocebus aethiops , Fluconazol/farmacologia , Iminas/síntese química , Iminas/química , Testes de Sensibilidade Microbiana , Células VeroRESUMO
α-Terpineol is a relatively cheap and abundant aroma compound. It is widely used in food, cosmetics, and household products. Many of its monoterpene counterparts have been applied in antiproliferative assays, leading to promising results in the prevention or even treatment of cancers. However, despite its theoretic potential, no paper reports the evaluation of antiproliferative capacity of this alcohol. Thus, antioxidant potential of three monoterpenoids (carvone, perillyl alcohol, and α-terpineol) was measured using two methods: DPPH and ORAC. Also, the antiproliferative effect of these monoterpenoids against nine cancerous cell lines were performed and compared to limonene and doxorubicin. Results showed that all samples tested had very low antioxidant activity in the DPPH assay, but α-terpineol (2.72µmolTrolox equiv./µmol) could be compared to commercial antioxidants in the ORAC assay. The antiproliferative results obtained encourage future in vivo studies for α-terpineol, since this monoterpenoid presented cytostatic effect against six cell lines, especially for breast adenocarcinoma and chronic myeloid leukemia, in a range of 181-588µM.
Assuntos
Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Cicloexenos/farmacologia , Monoterpenos/farmacologia , Compostos de Bifenilo/farmacologia , Monoterpenos Cicloexânicos , Células HT29 , Humanos , Células K562 , Picratos/farmacologiaRESUMO
Pancreas transplantation is currently the only known therapy to restore glycemic metabolism in type 1 diabetic patients. Its most prevalent indication is in association with kidney transplantation (simultaneous pancreas and kidney transplantation SPK) for patients with type 1 diabetes mellitus (DM1) and nephropathy, who are under dialysis treatment. Surgical reinterventions, especially those resulting from complications of bladder exocrine pancreatic drainage, are associated with considerable morbidity and mortality. In this report, we present a clinical case of a 31-year-old Caucasian man with DM1 from 12 years of age and hemodialysis for 2 years before undergoing SPK 2 years prior. He then developed massive hematuria owing to a bleeding duodenal graft ulcer. The use of a segmental pancreatic technique with pancreaticocystostomy for exocrine pancreatic drainage allowed the maintenance of the graft and an euglycemic state in the patient, free of exogenous insulin.
Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Nefropatias Diabéticas/cirurgia , Nefropatias Diabéticas/terapia , Adulto , Antivirais/uso terapêutico , Cistostomia , Infecções por Citomegalovirus/tratamento farmacológico , Duodeno/cirurgia , Ganciclovir/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Masculino , Transplante de Pâncreas/imunologia , Pancreatectomia/métodos , Complicações Pós-OperatóriasRESUMO
Nature is an inexhaustible source of natural compounds with interesting biological activities. In general, natural products are an important source of new compounds with a variety of structural arrangements and singular properties. Styryl lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess interesting biological properties, in particular antiproliferative activity against cancer cells. In general, the cytotoxicity of styryl lactones appears to be specific against cancer cells since insignificant effects of these compounds on normal cells are reported. A large body of evidence suggests that the antiproliferative activity of styryl lactones is associated with the induction of apoptosis in target cells. In the first part of this review we discuss the biological activities of styryl lactones focusing on cancer cells, the causal agent of Chagas' disease and the vectors for yellow fever and human lymphatic filariasis. Stru described in detail for ninety styryl lactones. The last part describes the molecular targets of styryl lactones for inducing apoptosis, as well as immunosuppressive and inflammatory processes. Overall, understanding how these compounds exert their activities in biological system is essential for future development and application of styryl lactones for human health.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Desenho de Fármacos , Lactonas/química , Lactonas/farmacologia , Linhagem Celular Tumoral , Humanos , Relação Estrutura-AtividadeRESUMO
In this work we report our results concerning the study on the in vitro antiproliferative activity of 18 Baylis-Hillman adducts and some derivatives against a panel of humor tumor cell lines. A brief qualitative structure-activity relationship study indicated that carbon-carbon double bond and the presence of an electron-withdrawing substituent at the aromatic ring are essential for the activity. A quinoline-phthalide derivative has exhibited a potent effect on the proliferation of all cell lines. It is interesting to note their special cytotoxic activity against NCIADR cell line.
Assuntos
Benzofuranos/farmacologia , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
The resulting enriched sesquiterpene lactone fraction and the crude ethanol extract of Artemisia annua L. aerial parts, showed antiulcerogenic activity when administered orally, on the indomethacin induced ulcer in rats. The sesquiterpene lactone fraction yielded three different polarity fractions on column chromatography as follows: non-polar, medium polarity and polar fraction, When submitted to the same indomethacin-induced ulcer in rats they resulted in different levels of inhibition of the ulcerative lesion index. The participation of nitric oxide was evaluated on an ethanol-induced ulcer model which had a previous administration of L-NAME, a NO-synthase inhibitor. Under these conditions, the medium polarity fraction maintained the antiulcerogenic activity, suggesting that nitric oxide could not be involved in the antiulcerogenic activity. When the animal groups were treated with N-ethylmaleimide, an alkylator of sulphhydryl groups, using the same experimental model, the medium polarity fraction maintained its antiulcerogenic activity, suggesting that the pharmacological mechanism is not related to non-protein sulphydryl compounds. On the ethanol-induced ulcer with previous indomethacin treatment, the medium polarity fraction lost its antiulcerogenic activity indicating that the active compounds of Artemisia annua L. increase the prostaglandin levels in the gastric mucosa. This hypothesis was reinforced by an increase of adherent mucus production by the gastric mucosa, produced by the medium polarity fraction on the hypothermic restraint stress induced ulcer model.