RESUMEN

A series of PdII complexes with bis-(2-pyridylmethyl)glycine as a ligand of formula [PdX(bis-(2-pyridylmethyl)glycine)] where X = 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 µM). 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.

Asunto(s)

Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Halógenos/química , Paladio/química , Péptidos/química , Péptidos/farmacología , Proteínas de Unión a Transferrina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Células HT29 , Humanos , Células MCF-7 , Espectroscopía de Resonancia Magnética , Péptidos/síntesis química , Relación Estructura-Actividad , Difracción de Rayos X

RESUMEN

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 3.04 nmol 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.

Asunto(s)

Antibacterianos , Antineoplásicos , Complejos de Coordinación , Oro , Bacterias Grampositivas/crecimiento & desarrollo , Fosfinas , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Oro/química , Oro/farmacología , Humanos , Células MCF-7 , Fosfinas/química , Fosfinas/farmacología , Albúmina Sérica Bovina/química

RESUMEN

Amphipterygium adstringens is a plant widely used in Mexican traditional medicine for its known anti-inflammatory and antiulcer properties. In this work, we evaluated the in vitro antimicrobial and antiproliferative activities of the methanolic extract of A. adstringens against oral pathogens such as Streptococcus mutans, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Candida albicans, and Candida dubliniensis, using microdilution (MIC) and agar diffusion methods (MBC), and the antiproliferative activity evaluating total growth inhibition (TGI) by staining the protein content with sulforhodamine B (SRB), using nine human cancer cell lines. Crude extract (CE) of A. adstringens showed some degree of activity against one or more of the strains with a MIC from 0.125 mg/mL to 63 mg/mL and MBC from 1.6 to 6.3 mg/mL and cytotoxic activity, particularly against NCI-ADR/RES, an ovarian cell line expressing multiple resistance drugs phenotype. The CE is a complex mixture of possible multitarget metabolites that could be responsible for both antimicrobial and antiproliferative activities, and further investigation is required to elucidate the identity of active compounds. Nevertheless the CE itself is useful in the development of new antimicrobial treatment based on natural products to prevent oral diseases and as alternative natural source for cancer treatment and prevention.

RESUMEN

PURPOSE: A proportion of patients with metastatic colorectal cancer (mCRC) are still able to continue with active therapy after their progression to fluoropyrimidines, oxaliplatin, and irinotecan regimens. Studies suggest that gemcitabine and fluoropyrimidines are synergic antimetabolites. The purpose was to evaluate gemcitabine-capecitabine (Gem-Cape) in heavily pretreated mCRC and to thus assess possible predictive factors for progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: This analysis was performed on 119 evaluable patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, and biological agents between June 2001 and July 2011. Patients received gemcitabine 1,000 mg/m(2) day 1 and capecitabine 1,000 mg/m(2) bid for 7 days every 2 weeks. RESULTS: The general characteristics were ECOG 0-1, 89 %; male, 68 %, and median age 63 years. In total, 61 % had received two chemotherapy lines, while 39 % had received three or more. Objective response rates and stable disease rates at 3 months were 6.72 and 37.81 %, equalling a clinical benefit of 44.53 %. The median PFS and OS were 2.87 months [95 % confidence interval (CI) 2.53-3.17 months] and 6.53 months (95 % CI 5.33-8.77), respectively. The most frequent toxicities were grades 1-2, anemia (22 %), thrombocytopenia (10 %), and hand-foot syndrome (9 %); grade ≥3, diarrhea (2 %), with no treatment-related discontinuations. No treatment-related deaths were reported. Statistical significance was obtained by subgroups, assessing clinical benefits and objective responses for PFS and OS. Moreover, patients under 65 tended to have a better PFS. CONCLUSION: These data suggest that Gem-Cape is a tolerable and feasible regimen, associated with clinical benefit in non-selected, heavily pretreated, mCRC patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias del Recto/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/secundario , Capecitabina/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias Peritoneales/secundario , Retratamiento , Estudios Retrospectivos , Tasa de Supervivencia , Gemcitabina

RESUMEN

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.

Asunto(s)

Antifúngicos/farmacología , Cryptococcus gattii/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Iminas/farmacología , Animales , Chlorocebus aethiops , Fluconazol/farmacología , Iminas/síntesis química , Iminas/química , Pruebas de Sensibilidad Microbiana , Células Vero

RESUMEN

Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative β-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed.

Asunto(s)

Animales , Humanos , Masculino , Ratones , Antineoplásicos/farmacología , Chromobacterium/metabolismo , Indoles/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Antineoplásicos/aislamiento & purificación , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Mezclas Complejas , Indoles/aislamiento & purificación , Indoles/uso terapéutico , Espectrometría de Masa por Ionización de Electrospray

RESUMEN

Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative ß-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed.

Asunto(s)

Antineoplásicos/farmacología , Chromobacterium/metabolismo , Indoles/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Mezclas Complejas , Humanos , Indoles/aislamiento & purificación , Indoles/uso terapéutico , Masculino , Ratones , Espectrometría de Masa por Ionización de Electrospray

RESUMEN

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.

Asunto(s)

Antioxidantes/farmacología , Proliferación Celular/efectos de los fármacos , Ciclohexenos/farmacología , Monoterpenos/farmacología , Compuestos de Bifenilo/farmacología , Monoterpenos Ciclohexánicos , Células HT29 , Humanos , Células K562 , Picratos/farmacología

RESUMEN

Este trabalho apresenta os resultados de atividade alelopática, antimicrobiana e antioxidante dos extratos orgânicos (hexano, acetato de etila e metanol) das folhas de Pyrostegia venusta (Ker Gawl.) Miers (Bignoniaceae). Para alelopatia, foi estudado o desenvolvimento de Cucumis sativus (pepino), sendo avaliados o comprimento da raiz principal, o número de raízes secundárias e o comprimento do hipocótilo. Os dois primeiros parâmetros foram afetados por todos os três extratos testados enquanto o comprimento do hipocótilo só não foi afetado pelo extrato acetato de etila. Quanto à atividade antimicrobiana, avaliada pelo ensaio de CIM, o extrato hexânico apresentou inibição moderada frente ao Staphylococcus aureus (0,9 mg mL-1) e forte ao Enterococcus hirae (0,5 mg mL-1). O extrato acetato de etila apresentou forte atividade frente Candida albicans (0,3 mg mL-1) enquanto o extrato metanólico não mostrou-se ativo para os microrganismos testados. Por outro lado, o extrato metanólico apresentou a maior capacidade de seqüestrar radicais livres (Concentração Efetiva 50 por cento-CE50 =102,0 ± 56,9 mg mL-1, com TCE50 = 30 min) no ensaio com DPPH (2,2-difenil-1-picril-hidrazila) e o maior teor de compostos fenólicos (116,2 ± 83,0 mg ácido gálico g amostra-1), avaliado pelo ensaio de Folin-Ciocalteau.

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This paper presents the results of allelopathic, antimicrobial and antioxidant activities of organic extracts (hexane, ethyl acetate and methanol) from the leaves of Pyrostegia venusta (Ker Gawl.) Miers (Bignoniaceae). Allelopathic activity was assessed based on Cucumis sativus (cucumber) development for the parameters main root length, number of secondary roots and hypocotyl length. All tested extracts affected the first two parameters, while the hypocotyl length was not affected only by the ethyl acetate extract. For antimicrobial activity, assessed by MIC assay, hexane extract showed moderate inhibition for Staphylococcus aureus (0.9 mg mL-1) and strong inhibition for Enterococcus hirae (0.5 mg mL-1). Ethyl acetate extract showed strong activity against Candida albicans (0.3 mg mL-1), whereas methanolic extract was not active against the tested microorganisms. On the other hand, methanol extract showed the most promising radical scavenging capacity (Effective Concentration 50 percent - EC50 = 102.0 ± 56.9 mg mL-1, with TEC50 = 30 min) in DPPH assay (2,2-diphenyl-1-picryl-hidrazil) and the highest level of phenolic compounds (116.2 ± 83.0 mg acid garlic g sample-1), as indicated by Folin-Ciocalteau assay.

Asunto(s)

Antibacterianos , Antioxidantes , Bignoniaceae , Feromonas/análisis , Técnicas In Vitro , Extractos Vegetales , Hojas de la Planta , Aberraciones Cromosómicas , Bioensayo/métodos , Pruebas de Micronúcleos

Asunto(s)

Comercialización de los Servicios de Salud , Farmacia , Investigación

RESUMEN

O gênero Eleocharis R. Br. compreende cerca de 200 espécies, ocorrendo em ambientes úmidos tais como brejos e margens de rios e lagos. Procurando novos agentes moluscicidas, os extratos de Eleocharis acutangula (Roxb.) Schult., Eleocharis interstincta (Vahl) Roem. & Schult., Eleocharis maculosa (Vahl) Roem. & Schult. e Eleocharis sellowiana Kunth foram testados para atividade moluscicida, contra caramujos adultos e desovas, e toxicidade (ensaio de letalidade com Artemia salina). O extrato hexânico de Eleocharis acutangula (parte subterrânea fresca) foi ativo contra Artemia salina (CL50 = 476,00 mg/mL), enquanto os demais extratos apresentaram CL50 >> 10³ mg/mL, sugerindo baixa toxicidade. O extrato hidro-etanólico de Eleocharis sellowiana (parte subterrânea fresca) foi ativo contra desovas de Biomphalaria glabrata (CL50 = 24,27 mg/mL) mas inativo contra indivíduos adultos. Os demais extratos testados não apresentaram atividade moluscicida.

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The genus Eleocharis R. Br. comprises about 200 species, occurring in wet environments like swamps, lakes and river margins. In the search for new molluscicides, extracts from Eleocharis acutangula (Roxb.) Schult., Eleocharis interstincta (Vahl) Roem. & Schult., Eleocharis maculosa (Vahl) Roem. & Schult. and Eleocharis sellowiana Kunth were tested for molluscicidal activity (spawns and adult snails) and toxicity (Brine Shrimp Lethality - BSL - bioassay). The hexane extract of Eleocharis acutangula (fresh subterraneous parts) was active in the BSL bioassay (LC50 = 476 mg/mL), while the other extracts showed LC50 >> 10³ mg/mL, suggesting they have low toxicity. The aqueous ethanol extract of Eleocharis sellowiana (fresh subterraneous parts) was active against Biomphalaria glabrata spawns (LC50 = 24.27 mg/mL) but it was not lethal to adult snails. No other plant extract tested in this study showed molluscicidal activity.

RESUMEN

Potential vectors of Leishmania braziliensis Vianna were assessed at four study sites in the mountainous Valle del Cauca, western Colombia, from March to June 1989. In an active focus of transmission at 1450 m altitude, a coffee plantation at Versalles, there were high densities of antropophilic phlebotomines: Lutzomyia columbiana (Ritorcelli & Van Ty) and Lu.townsendi (Ortiz), both in the verrucarum species group, and of Lu.pia (Fairchild & Hertig). At a comparable altitude in a forest reserve at Yotoco where leishmaniasis is unknown, Lu.pia was the prevalent species and Lu.townsendi was absent. In two localities at 1150 m altitude, there were plentiful Lu.lichyi (Floch & Abonnenc) plus both species in the verrucarum group, but Lu.pia was absent. One of these localities, a coffee plantation at Villa Hermosa where a leishmaniasis outbreak occurred in 1986, was compared with a leishmaniasis-free, partly wooded nature reserve at Mateguadua. No natural infections of Leishmania were found in a total of 1896 wild-caught female phlebotomines belonging to at least seven species. It remains unclear why Leishmaniasis transmission is associated with coffee plantations in this part of Colombia. Laboratory-bred Lu.lichyi females were invariably autogenous, and blood-seeking females of this species were always parous. Parity rates in wild-caught females of other species were 55% Lu.pia, 24% Lu.columbiana and 14% Lu.townsendi. Female Lutzomyia infected artificially with Le.braziliensis promastigotes developed peripylarian infections. Higher proportions of Lu.townsendi (96%) and Lu.columbiana (78%) became infected but these species developed lower rates of stomodaeal infections (P less than 0.1) than Lu.lichyi (37%) or Lu.pia (44%).(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Insectos Vectores/parasitología , Leishmania/aislamiento & purificación , Leishmaniasis/transmisión , Psychodidae/parasitología , Animales , Femenino , Insectos Vectores/fisiología , Psychodidae/fisiología

RESUMEN

Sera from 223 human beings were assayed by enzyme-linked immunosorbent assay for immunoglobulin G antibodies to Leishmania mexicana mexicana promastigotes. 76% of 74 sera from patients with chiclero's ulcer gave positive reactions at a titre of 1:40; the positivity rate was lower in patients with long-standing infections. False positive reactions were obtained with only 7% of 56 sera from healthy individuals with positive Montenegro tests and with 6 of 7 sera from patients with Chagas disease. It is concluded that this method would be a useful contributory diagnostic method in cases of suspected chiclero's ulcer.

Asunto(s)

Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina G/inmunología , Leishmania mexicana/inmunología , Leishmaniasis/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Antiprotozoarios/análisis , Especificidad de Anticuerpos , Enfermedad de Chagas/inmunología , Niño , Reacciones Cruzadas , Humanos , México , Persona de Mediana Edad , Sensibilidad y Especificidad

Asunto(s)

Recuento de Células/métodos , Calostro/citología , Macrófagos/citología , Adhesión Celular , Femenino , Humanos

Asunto(s)

Leishmaniasis/patología , Adolescente , Adulto , Antígenos/análisis , Granuloma/etiología , Granuloma/patología , Humanos , Hipergammaglobulinemia/etiología , Inmunidad Celular , Leishmania/inmunología , Leishmaniasis/complicaciones , Leishmaniasis/inmunología , Masculino , Persona de Mediana Edad , Recurrencia

RESUMEN

Se estudiaron un total de siete pacientes provenientes de area endemica y con cuadro clinico de leishmaniasis cutanea mexicana.Se les practicaron historia clinioepidemiologica, biopsia, evaluacion de perfil inmunologico (linfocitos T y B, determinacion de inmunoglobulinas y C3) y reaccion inmunitaria especifica (intradermorreaccion de Montenegro y ELISA). Clinicamente no se encontraron diferencias con lo informado en la literatura. El patron histopatologico es caracteristico y diferente a lo encontrado en otras leishmaniasis cutaneas. Inmunologicamente los hallazgos sobresalientes fueron hipergammaglobulinemia en 6/7 (85.71 por ciento) y ELISA positivo en 5/7 (71.42 por ciento). Se discuten las posibles correlaciones y se proponen criterios diagnosticos

Asunto(s)

Adolescente , Adulto , Persona de Mediana Edad , Humanos , Leishmaniasis , México

Asunto(s)

Humanos , Femenino , Calostro , Macrófagos