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1.
Sci Rep ; 9(1): 11813, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413300

RESUMO

Sickle cell anaemia (SCA) is characterized by reduced red blood cell (RBC) deformability and nitric oxide (NO) bioavailability. The aim of the study was to investigate whether exercise might affect these parameters in SCA. SCA patients and healthy controls (AA) performed an acute submaximal exercise test until subjects reached the first ventilatory threshold (VT 1). Blood was sampled at rest and at VT 1. At rest, free haemoglobin level was higher and RBC count, haemoglobin and haematocrit were lower in SCA compared to AA. RBC deformability was lower in SCA. Exercise had no effect on the tested parameters. RBC NO level was higher in SCA compared to AA at rest and significantly decreased after exercise in SCA. This might be related to a reduction in RBC-NO synthase (RBC-NOS) activation which was only observed in SCA after exercise. Free radical levels were higher in SCA at rest but concentration was not affected by exercise. Marker for lipid peroxidation and antioxidative capacity were similar in SCA and AA and not affected by exercise. In conclusion, a single acute submaximal bout of exercise has no deleterious effects on RBC deformability or oxidative stress markers in SCA, and seems to modulate RBC-NOS signalling pathway.

3.
Klin Padiatr ; 231(3): 142-149, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30544267

RESUMO

BACKGROUND: With improved survival rates in pediatric oncology, the detection of adverse side- and late-effects is gaining increased interest. This cross-sectional study investigated walking abilities and ankle dorsiflexion function in children with cancer. PATIENTS: Study participants included 16 children with various cancers (4-20 years, patient group) after completion of the intense treatment and 16 age- and gender-matched healthy peers (comparison group). METHOD: Walking speed (10-meter-walking-test, treadmill test assessing preferred transition speed), walking capacity (2-minute-walk-test), walking balance (Timed-Up-And-Go-Test), active/passive ankle dorsiflexion range of motion (ROM) (goniometer) and ankle dorsiflexion strength (hand-held dynamometer) were comprehensively assessed. RESULTS: Significant lower values in the patient group were found for walking capacity, maximum walking speed, ankle dorsiflexion ROM and strength. No significant differences between the groups were found for preferred walking speed and walking balance. DISCUSSION: Limited walking abilities and ankle dorsiflexion dysfunctions are prominent in children with cancer; having the potential to impact children's community mobility and physical activity. CONCLUSIONS: To provide holistic care, the development of specific supportive strategies such as exercise interventions and its translation into clinical practice needs to be accelerated.


Assuntos
Articulação do Tornozelo/fisiopatologia , Tornozelo , Amplitude de Movimento Articular/fisiologia , Caminhada/fisiologia , Antineoplásicos/uso terapêutico , Criança , Estudos Transversais , Exercício , Marcha/fisiologia , Humanos , Neoplasias/terapia
4.
Metallomics ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30516775

RESUMO

Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorganic chemistry based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogues. The complex is highly stable in various solutions over 96 hours, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time. A portfolio of other gold complexes (e.g. Auranofin) has been used as references in key biological assays, showing that the novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity.

5.
Pediatr Phys Ther ; 30(4): 341-349, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30277971

RESUMO

PURPOSE: To assess a whole-body vibration (WBV) intervention for children after cancer treatment. METHODS: Eleven children after inpatient anticancer therapy participated in a 12-week supervised WBV intervention, which consisted of one 9- to 13-minute WBV session per week, with 5 to 9 minutes' overall vibration time. Feasibility was defined as the ability to participate in WBV training without reporting adverse events. The number of offered and completed training sessions, program acceptance, and measures of function were assessed. RESULTS: Nine participants completed the WBV intervention without any WBV-related adverse events. The adherence rate was 87.96%. Only minor side effects were reported and there was general program acceptance. We found indications that WBV has positive effects on knee extensor strength and active ankle dorsiflexion range of motion. CONCLUSIONS: WBV was feasible, safe, and well received among children after inpatient anticancer therapy. No health deteriorations were observed. Positive effects need to be confirmed in future trials.

6.
Medchemcomm ; 9(1): 173-180, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108911

RESUMO

Emerging resistances of tumors against multiple anti-cancer agents are a major concern in the chemotherapeutical treatment of various cancers. Clearly, this raises the need for novel therapeutics with new modes of action. Herein, we report on the favorable in vitro anti-proliferative properties of a phenanthridine-containing ReI(CO)3 complex (compound 1, also abbreviated LR-166) and identify major contributions to its mode of action. The complex induces apoptosis in low micromolar concentrations even in drug-resistant Burkitt-like lymphoma (BJAB) and leukemia (Nalm-6) cell lines with known overexpression of p-glycoproteins as was confirmed by measuring the amount of hypodiploid DNA via FACS Scan analysis. Importantly, a gene expression analysis in combination with toxicity studies on a number of modified cell lines (leukemia: NALM-6, lymphoma: BJAB, melanoma: MelHO) and the reduction of mitochondrial membrane potential (determined by adding JC-1 dye, followed by FACS analysis) confirmed the activation of both, the extrinsic and the intrinsic apoptotic pathway. Finally, the mechanism of action was shown not to be influenced by overexpression of the anti-apoptotic factor Bcl-2 in Mel-HO cells which are known to be resistant to a variety of drugs. All taken together, our experiments underscore the unique opportunities inherent in this novel lead structure of Re complexes to act as an effective chemotherapeutic agent in a combination therapy to overcome documented drug resistances in tumors.

7.
Leuk Lymphoma ; : 1-7, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29718744

RESUMO

Osteonecrosis (ON) is a common and debilitating side effect of anti-leukemic treatment in children with acute lymphoblastic leukemia (ALL). However, the impact of leukemia itself on ON development remains elusive. We analyzed 76 children enrolled in the ongoing OPAL trial, who had magnetic resonance imaging (MRI) studies at diagnosis. MRI screening revealed 14 osteonecrotic lesions (5 × hips, 9 × knees) of any grade (I-III) in 7 (9.2%) patients. Six months on, the number of ON per patient increased (1 patient), remained constant (2), and decreased (2). The severity increased from grade I to II in two patients, remained constant (1), completely resolved (2), and decreased from grade III to osteoedema (1). No differences between adolescents initially presenting with/without ON were observed concerning age, pubertal stage, body mass index, leukemia characteristics, and clinical presentation. In MRI screening, a remarkable number of adolescents with ALL present with ON at diagnosis. The course of these ON remains highly unpredictable.

8.
J Cancer Res Clin Oncol ; 144(4): 685-695, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29374786

RESUMO

PURPOSE: We report on our preclinical findings of a simple salicylic diamine compound (THG 1213) which has yielded exceptional results as a potential chemotherapeutic drug. THG 1213 is an easy to synthesize chiral and metal-free salan compound. METHODS: THG 1213 was tested on several leukemia, lymphoma and solid tumor cell lines in vitro. The effects have been studied by LDH release essay, FACS flow cytometry, photometric cell count, immunoblotting, and NMR spectroscopy. RESULTS: THG 1213 selectively inhibits proliferation and induces apoptosis in leukemia, lymphoma and solid tumor cell lines. Necrosis or effects on healthy leucocytes could not be detected. Apoptosis is induced via the intrinsic and extrinsic pathways. The salan THG 1213 overcomes multidrug resistance in tumor cells and acts synergistically with vincristine and daunorubicin. CONCLUSIONS: THG 1213 displays remarkable antitumor properties. In particular, the lack of metallic components of THG 1213 could prove to be beneficial in future clinical trials, as metal-containing drugs are known to show severe side effects.


Assuntos
Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Fenilenodiaminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Daunorrubicina/administração & dosagem , Daunorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Leucemia/patologia , Linfoma/patologia , Neoplasias/tratamento farmacológico , Fenilenodiaminas/administração & dosagem , Salicilatos/administração & dosagem , Salicilatos/farmacologia , Vincristina/administração & dosagem , Vincristina/farmacologia
9.
ChemMedChem ; 12(3): 214-225, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-27997743

RESUMO

Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(1,5-cyclooctadiene)(NHC)RhCl)] (4 a-c), [(p-cymene)(NHC)RuCl2 )] (5 a-c), and [(NHC)CuBr] (6 a-c) were synthesized and investigated as antiproliferative agents that target DNA. The cytotoxic effects were largely driven by the naphthalimide structure, which is a DNA-intercalating moiety. Regarding the metal center, the highest activities were observed with the rhodium complexes, and cytotoxic activity was significantly lower for the ruthenium derivatives. The stable coordination of the NHC ligands of selected complexes 4 b and 5 b in solution was confirmed, and their DNA binding properties were studied by UV/Vis spectroscopy, mass spectrometry, and circular dichroism. Stable intercalative binding into the DNA for all selected naphthalimide-based complexes is indicated by high DNA binding constants. Particularly efficient binding was observed in the case of the rhodium complex 4 b. More detailed biological studies on 4 b showed promising activities against multidrug-resistant Nalm-6 cells and confirmed an important role for mitochondrial pathways in 4 b-induced apoptosis.


Assuntos
Complexos de Coordenação/química , DNA/química , Substâncias Intercalantes/química , Metano/análogos & derivados , Naftalimidas/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , DNA/metabolismo , Estabilidade de Medicamentos , Células HT29 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/toxicidade , Ligantes , Células MCF-7 , Metano/química , Conformação Molecular , Monoterpenos/química , Ródio/química , Rutênio/química , Espectrofotometria Ultravioleta
10.
Chemistry ; 23(8): 1869-1880, 2017 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-27865002

RESUMO

Gold complexes with N-heterocyclic carbene (NHC) ligands represent a promising class of metallodrugs for the treatment of cancer or infectious diseases. In this report, the synthesis and the biological evaluation of halogen-containing NHC-AuI -Cl complexes are described. The complexes 1 and 5 a-5 f displayed good cytotoxic activity against tumor cells, and cellular uptake studies suggested that an intact Au-NHC fragment is essential for the accumulation of high amounts of both the metal and the NHC ligand. However, the bioavailability was negatively affected by serum components of the cell culture media and was influenced by likely transformations of the complex. One example (5 d) efficiently induced apoptosis in vincristine- and daunorubicin-resistant P-glycoprotein overexpressing Nalm-6 leukemia cells. Cellular uptake studies with this compound showed that both the wild-type and resistant Nalm-6 cells accumulated comparable amounts of gold, indicating that the gold drug was not excreted by P-glycoprotein or other efflux transporters. The effective inhibition of mammalian and bacterial thioredoxin reductases (TrxR) was confirmed for all of the gold complexes. Antibacterial screening of the gold complexes showed a particularly high activity against Gram-positive strains, reflecting their high dependence on an intact Trx/TrxR system. This result is of particular interest as the inhibition of bacterial TrxR represents a relatively little explored mechanism of new anti-infectives.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/química , Proteínas de Bactérias/antagonistas & inibidores , Complexos de Coordenação/química , Ouro/química , Bactérias Gram-Positivas/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/química , Humanos , Metano/análogos & derivados , Metano/química , Testes de Sensibilidade Microbiana , Tiorredoxina Dissulfeto Redutase/metabolismo
11.
Medchemcomm ; 8(8): 1681-1689, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108879

RESUMO

A series of gold(i) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepared and evaluated for their effects against cancer cells and pathogenic bacteria. Proliferation inhibition was observed in cancer cells and in Gram-positive bacteria, whereas Gram-negative bacteria were less sensitive towards the compounds. The protein binding and cellular uptake were quantified and the combined results indicated a strong correlation between cellular bioavailability and antiproliferative effects. The biscarbene gold complexes inhibited bacterial and mammalian TrxRs with low to moderate potency. However, based on the obtained structure-activity-relationships and the high cellular accumulation levels, TrxR inhibition can be considered as a relevant contributor to the cellular pharmacology of biscarbene gold(i) complexes.

12.
Pediatr Blood Cancer ; 63(1): 127-32, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26184456

RESUMO

BACKGROUND: Exercise interventions in pediatric oncology are feasible and safe. However, scarce data are available with regard to the effectiveness of outpatient, group-based exercise interventions. As well, the potential role of exercise to improve motor performance has not been adequately explored despite being a meaningful outcome during childhood with important implications for physical activity behavior. No study has yet demonstrated significant changes in motor performance after an exercise intervention. PROCEDURES: This explorative, prospective study was designed to evaluate the effects of a 6-month, group-based, therapeutic exercise program for a mixed childhood cancer population on motor performance, level of activity, and quality of life. After cessation of inpatient medical treatment, childhood cancer outpatients aged 4-17 years exercised once a week during a 6-month period (IG). Comparison groups included childhood cancer outpatients receiving care as usual (CG(1)), as well as healthy peers (matched to IG by age and gender) (CG(2)). RESULTS: Overall motor performance, various motor dimensions, activity in sport clubs and school sports, as well as physical and emotional well-being were significantly reduced in the IG at baseline. Significant differences between the IG and CG(1) and/or CG(2) were identified in the change of overall motor performance, single motor dimensions, overall level of activity, and emotional well-being from baseline to post-intervention. CONCLUSIONS: The exercise intervention was beneficial in terms of motor performance, level of activity, and emotional well-being. As such, this study provides support for group-based exercise as a potential strategy to improve these outcomes after inpatient medical treatment.


Assuntos
Exercício , Neoplasias/terapia , Desempenho Psicomotor , Qualidade de Vida , Adolescente , Criança , Pré-Escolar , Emoções , Feminino , Processos Grupais , Humanos , Masculino , Pacientes Ambulatoriais , Estudos Prospectivos
13.
Cancer Nurs ; 39(2): 117-24, 2016 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25881810

RESUMO

BACKGROUND: Improvements in survival rates in pediatric oncology have resulted in a growing need to identify adverse effects and improve rehabilitation in this population. OBJECTIVE: This cross-sectional study aimed to investigate active ankle dorsiflexion (DF) range of motion (ROM), gait, walking efficiency, and motor performance in a mixed childhood cancer survivor population in comparison to healthy peers. METHODS: Active ankle DF-ROM (goniometer), gait (Microgate Optogait 2D Gait Analysis), walking efficiency (6-minute walk test), and motor performance (German Motor Test 6-18) were assessed in a mixed childhood cancer survivor population after cessation of medical treatment (n = 13) in comparison to healthy children matched for age and gender (n = 13). RESULTS: Active ankle DF-ROM, gait (stance, swing, and preswing phase), and walking efficiency were significantly impaired in survivors compared with control subjects. No significant difference between groups was found in motor performance. CONCLUSION: Despite sufficient total motor performance levels, specific limitations in physical functioning were identified in a mixed childhood cancer survivor sample. This highlights the importance of the present findings. IMPLICATION FOR PRACTICE: The results from this study highlight the potential significance of limited ankle DF function, inhibited gait, and reduced walking efficiency as adverse effects of various types of childhood cancer. It is hoped this enhanced recognition by pediatric cancer patients, parents, and exercise professionals will initiate specific supportive strategies and potentially prevent further limitations.


Assuntos
Articulação do Tornozelo/fisiopatologia , Marcha/fisiologia , Neoplasias/fisiopatologia , Amplitude de Movimento Articular/fisiologia , Sobreviventes/estatística & dados numéricos , Caminhada/fisiologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Neoplasias/enfermagem , Neoplasias/terapia
14.
Mol Cancer ; 14: 114, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-26041471

RESUMO

BACKGROUND: Redox stress is a hallmark of the rewired metabolic phenotype of cancer. The underlying dysregulation of reactive oxygen species (ROS) is interconnected with abnormal mitochondrial biogenesis and function. In chronic lymphocytic leukemia (CLL), elevated ROS are implicated in clonal outgrowth and drug resistance. The pro-survival oncogene T-cell leukemia 1 (TCL1) is causally linked to the high threshold towards classical apoptosis in CLL. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable. METHODS: Bio-organometallic chemistry provided compounds containing a cytosine nucleobase, a metal core (ferrocene, ruthenocene, Fe(CO)3), and a 5'-CH2O-TDS substituent. Four of these metal-containing nucleoside analogues (MCNA) were tested for their efficacy and mode of action in CLL patient samples, gene-targeted cell lines, and murine TCL1-transgenic splenocytes. RESULTS: The MCNA showed a marked and selective cytotoxicity towards CLL cells. MCNA activity was equally observed in high-risk disease groups, including those of del11q/del17p cytogenetics and of clinical fludarabine resistance. They overcame protective stromal cell interactions. MCNA-evoked PARP-mediated cell death was non-autophagic and non-necrotic as well as caspase- and P53-independent. This unconventional apoptosis involved early increases of ROS, which proved indispensible based on mitigation of MCNA-triggered death by various scavengers. MCNA exposure reduced mitochondrial respiration (oxygen consumption rate; OCR) and induced a rapid membrane depolarization (∆ΨM). These characteristics distinguished the MCNA from the alkylator bendamustine and from fludarabine. Higher cellular ROS and increased MCNA sensitivity were linked to TCL1 expression. The presence of TCL1 promoted a mitochondrial release of in part caspase-independent apoptotic factors (AIF, Smac, Cytochrome-c) in response to MCNA. Although basal mitochondrial respiration (OCR) and maximal respiratory capacity were not affected by TCL1 overexpression, it mediated a reduced aerobic glycolysis (lactate production) and a higher fraction of oxygen consumption coupled to ATP-synthesis. CONCLUSIONS: Redox-active substances such as organometallic nucleosides can confer specific cytotoxicity to ROS-stressed cancer cells. Their P53- and caspase-independent induction of non-classical apoptosis implicates that redox-based strategies can overcome resistance to conventional apoptotic triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial energetic flux and renders them more susceptible towards agents interfering in mitochondrial homeostasis.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Mitocôndrias/metabolismo , Nucleosídeos/farmacologia , Oncogenes , Compostos Organometálicos/farmacologia , Proteínas Proto-Oncogênicas/genética , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Necrose , Nucleosídeos/química , Compostos Organometálicos/química , Fatores de Risco , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Proteína Supressora de Tumor p53/metabolismo
15.
Int J Parasitol Drugs Drug Resist ; 5(2): 48-57, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25949928

RESUMO

Malaria remains one of the most deadly diseases threatening humankind and is still affecting a significant proportion of the world population, especially in Africa. Chemotherapy is a vital component of the fight against the disease and new antimalarial agents are urgently needed to curb the spread of malaria parasites that are resistant to existing drugs. The natural product tryptanthrin is known for its wide range of activities, including antiplasmodial activity, but its poor solubility has undermined its development as potent antimicrobial and antiprotozoan agent. The aim of this work was to synthesize analogues of tryptanthrin and to evaluate their antiplasmodial activity against the asexual and sexual blood stages of Plasmodium falciparum. Our results suggest that most tryptanthrin analogues retained their antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant malaria parasites in the nanomolar range (30-100 nM). The antiplasmodial activity of the most active compound NT1 (IC50: 30 nM; SI: 155.9) was similar in both strains and close to that of chloroquine (IC50: 20 nM) on the sensitive strain. The antiplasmodial activity was improved with derivatization, thus pointing out the necessity to explore tryptanthrin using medicinal chemistry approaches. Ten (10) of the tested derivatives met the criteria, allowing for advancement to animal testing, i.e., SI > 100 and IC50 < 100 nM. In addition to their activity on the asexual stages, tryptanthrin and two selected derivatives (NT1 and T8) prevented the maturation of gametocytes at their IC90 concentrations, indicating a transmission-blocking potential. Moreover, NT1 was able to impair gametogenesis by reducing the exflagellation of microgametes by 20% at IC90, while tryptanthrin and T8 had no influence on exflagellation. The results of this study confirm that tryptanthrin and its derivatives are potential antimalarial candidates with abilities to kill the intraerythrocytic asexual stages and prevent the formation of sexual stages of the parasite.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistência a Medicamentos , Humanos , Estrutura Molecular
16.
Dalton Trans ; 44(3): 1161-9, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25413270

RESUMO

Gold(i) complexes with phosphane and thiotetrazolate ligands were prepared and investigated as a new type of bioactive gold metallodrugs. The complexes triggered very efficient inhibition of the enzyme thioredoxin reductase (TrxR), which is an important molecular target for gold species. Strong cytotoxic effects were observed in MDA-MB-231 breast adenocarcinoma and HT-29 colon carcinoma cells, and the complexes also caused strong effects in vincristine resistant Nalm-6 leukemia cells. Cellular uptake studies showed elevated cellular gold levels for complexes containing a triphenylphosphane ligand, whereas trifurylphosphane analogues accumulated at significantly lower cellular concentrations.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Inibidores Enzimáticos/química , Ouro/química , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Células HT29 , Humanos , Conformação Molecular , Fosfinas/química , Tiorredoxina Dissulfeto Redutase/metabolismo
17.
Eur J Med Chem ; 87: 794-800, 2014 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-25440880

RESUMO

Di-n-butyltin(IV) carboxylate and tri-n-butyltin(IV) carboxylate derivatives have demonstrated strong cytotoxic effects in different types of tumor cells. Complexes with carboxylate ligands that contain maleimide and naphthalimide derived partial structures were synthesized, characterized and investigated for inhibition of the tumor-relevant enzyme thioredoxin reductase and antiproliferative effects in cancer cells. The complexes were moderate inhibitors of thioredoxin reductase with activities in the micromolar range and triggered strong cytotoxic effects in MCF-7 breast cancer and HT-29 colon carcinoma cells. Interestingly, selected complexes were highly active in vincristine and daunorubicin resistant Nalm-6 cells.


Assuntos
Ácidos Carboxílicos/metabolismo , Maleimidas/química , Naftalimidas/química , Compostos Orgânicos de Estanho/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Compostos Orgânicos de Estanho/química , Espectrometria de Massas por Ionização por Electrospray
18.
Beilstein J Org Chem ; 10: 1630-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25161720

RESUMO

An operationally simple, convenient, and mild strategy for the synthesis of triazole-substituted titanocenes via strain-driven 1,3-dipolar cycloadditions between azide-functionalized titanocenes and cyclooctyne has been developed. It features the first synthesis of titanocenes containing azide groups. These compounds constitute 'second-generation' functionalized titanocene building blocks for further synthetic elaboration. Our synthesis is modular and large numbers of the complexes can in principle be prepared in short periods of time. Some of the triazole-substituted titanocenes display high cyctotoxic activity against BJAB cells. Comparison of the most active complexes allows the identification of structural features essential for biological activity.

19.
Chemistry ; 19(52): 17871-80, 2013 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-24243420

RESUMO

Rhodium(I) complexes bearing N-heterocyclic carbene (NHC) ligands have been widely used in catalytic chemistry, but there are very few reports of biological properties of these organometallics. A series of Rh(I)-NHC derivatives with 1,5-cyclooctadiene and CO as secondary ligands were synthesized, characterized, and biologically investigated as prospective antitumor drug candidates. Pronounced antiproliferative effects were noted for all complexes, along with moderate inhibitory activity of thioredoxin reductase (TrxR) and efficient binding to biomolecules (DNA, albumin). Biodistribution studies showed that the presence of albumin lowered the cellular uptake and confirmed the transport of rhodium into the nuclei. Changes in the mitochondrial membrane potential (MMP) were observed as well as DNA fragmentation in wild-type and daunorubicin- or vincristine-resistant Nalm-6 leukemia cells. Overall, these studies indicated that Rh(I)-NHC fragments could be used as partial structures of new antitumor agents, in particular in those drugs designed to address resistant malignant tissues.


Assuntos
Antineoplásicos/química , Metano/análogos & derivados , Ródio/química , Antineoplásicos/farmacologia , Humanos , Metano/química , Ródio/farmacologia
20.
Chemistry ; 19(39): 13017-29, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-23934861

RESUMO

The synthesis and stereochemical assignment of two classes of iron-containing nucleoside analogues, both of which contain a butadiene-Fe(CO)3 substructure, is described. The first type of compounds are Fe(CO)3-complexed 3'-alkenyl-2',3'-dideoxy-2',3'-dehydro nucleosides (2,5-dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH2 group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal-assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl-glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson-Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X-ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis-inducing properties (through an unusual caspase 3-independent but ROS-dependent pathway). Furthermore, some structure-activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin-labeled conjugates.


Assuntos
Biotina/síntese química , Corantes Fluorescentes/síntese química , Ferro/química , Metaloproteínas/síntese química , Metaloproteínas/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Apoptose/efeitos dos fármacos , Biotina/química , Corantes Fluorescentes/química , Espectroscopia de Ressonância Magnética , Metaloproteínas/química , Estrutura Molecular , Nucleosídeos/química , Relação Estrutura-Atividade , Difração de Raios X
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