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1.
Biochem Biophys Res Commun ; 559: 210-216, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33957482

RESUMO

In cancer therapeutics, boron neutron capture therapy (BNCT) requires a platform for selective and efficient 10B delivery into tumor tissues for a successful treatment. However, the use of carborane, a promising candidate with high boron content and biostability, has significant limitations in the biomedical field due to its poor water-solubility and tumor-selectivity. To overcome these hurdles, we present in this study a fluorescent nano complex, combining fluorescent carborane and sodium hyaluronate for high boron concentration and tumor-selectivity. Tumor cells actively internalized the complex through binding hyaluronan to CD44, overexpressed on the tumor cell surface. Furthermore, the subcellular distribution of this complex could also be detected due to its fluorescent properties. Moreover, after thermal neutron irradiations, the complex produced excellent cytotoxicity, equal to or greater than that of the clinically-used BPA-fructose. Therefore, this novel complex could be potentially more suitable for BNCT than the boron agent.


Assuntos
Boranos/uso terapêutico , Terapia por Captura de Nêutron de Boro , Ácido Hialurônico/uso terapêutico , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Ácido Hialurônico/ultraestrutura , Camundongos , Células RAW 264.7
2.
Toxicology ; 456: 152750, 2021 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-33737140

RESUMO

Paraquat, an herbicide used extensively worldwide, can cause severe toxicity in humans and animals, leading to irreversible, lethal lung fibrosis. The potential of CO-releasing molecules (CORMs), substances that release CO (Carbon monoxide) within animal tissues, for treating paraquat-induced ROS generation and inflammation is investigated here. Our results show that the fast CO releaser CORM-3 (4-20 µM) acts as a potential scavenger of free radicals and decreases fibrosis progression by inhibiting paraquat-induced overexpression of connective tissue growth factor and angiotensin II in MRC-5 cells. The slow CO releaser CORM-A1 (5 mg/kg) clearly decreased expression of the lung profibrogenic cytokines COX-2, TNF-α, and α-SMA and serum hydroxyproline, resulting in a lower mortality rate in paraquat-treated mice. Mice treated with higher-dose CORM-A1 (10 mg/kg) had relatively intact lung lobes and fewer fibrotic patches by gross observation, with less collagen deposition, mesangial matrix accumulation, and pulmonary fibrosis resulting from the mitigation of TGF-ß overexpression. In conclusion, our data demonstrate for the first time that CORM-A1 alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ, would be an attractive therapeutic approach to attenuate the progression of pulmonary fibrosis following PQ exposure.


Assuntos
Boranos/uso terapêutico , Monóxido de Carbono , Carbonatos/uso terapêutico , Herbicidas/toxicidade , Doenças Pulmonares Intersticiais/induzido quimicamente , Paraquat/toxicidade , Fibrose Pulmonar/induzido quimicamente , Animais , Boranos/farmacologia , Monóxido de Carbono/metabolismo , Carbonatos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Distribuição Aleatória
3.
Br J Radiol ; 93(1111): 20200311, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32374629

RESUMO

Boron neutron capture therapy (BNCT) has great potential to selectively destroy cancer cells while sparing surrounding normal cells. The basic concept of BNCT was developed in the 1930s, but it has not yet been commonly used in clinical practice, even though there is now a large number of experimental and translational studies demonstrating its marked therapeutic potential. With the development of neutron accelerators that can be installed in medical institutions, accelerator-based BNCT is expected to become available at several medical institutes around the world in the near future. In this commentary, from the point of view of radiation microdosimetry, we discuss the biological effects of BNCT, especially the underlying mechanisms of compound biological effectiveness. Radiobiological perspectives provide insight into the effectiveness of BNCT in creating a synergy effect in the field of clinical oncology.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias/radioterapia , Boranos/uso terapêutico , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro/instrumentação , Fluordesoxiglucose F18 , Humanos , Método de Monte Carlo , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Radiobiologia , Eficiência Biológica Relativa
4.
Theranostics ; 9(13): 3918-3939, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281522

RESUMO

Carbon monoxide and nitric oxide are two of the most important vasoprotective mediators. Their downregulation observed during vascular dysfunction, which is associated with cancer progression, leads to uncontrolled platelet activation. Therefore, the aim of our studies was to improve vasoprotection and to decrease platelet activation during progression of mouse mammary gland cancer by concurrent use of CO and NO donors (CORM-A1 and DETA/NO, respectively). Methods: Mice injected intravenously with 4T1-luc2-tdTomato or orthotopically with 4T1 mouse mammary gland cancer cells were treated with CORM-A1 and DETA/NO. Ex vivo aggregation and activation of platelets were assessed in the blood of healthy donors and breast cancer patients. Moreover, we analyzed the compounds' direct effect on 4T1 mouse and MDA-MB-231 human breast cancer cells proliferation, adhesion and migration in vitro. Results: We have observed antimetastatic effect of combination therapy, which was only transient in orthotopic model. During early stages of tumor progression concurrent use of CORM-A1 and DETA/NO demonstrated vasoprotective ability (decreased endothelin-1, sICAM and sE-selectin plasma level) and downregulated platelets activation (decreased bound of fibrinogen and vWf to platelets) as well as inhibited EMT process. Combined treatment with CO and NO donors diminished adhesion and migration of breast cancer cells in vitro and inhibited aggregation as well as TGF-ß release from breast cancer patients' platelets ex vivo. However, antimetastatic effect was not observed at a later stage of tumor progression which was accompanied by increased platelets activation and endothelial dysfunction related to a decrease of VASP level. Conclusion: The therapy was shown to have antimetastatic action and resulted in normalization of endothelial metabolism, diminution of platelet activation and inhibition of EMT process. The effect was more prominent during early stages of tumor dissemination. Such treatment could be applied to inhibit metastasis during the first stages of this process.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Boranos/farmacologia , Carbonatos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Óxido Nítrico/metabolismo , Compostos Nitrosos/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Boranos/uso terapêutico , Carbonatos/uso terapêutico , Bovinos , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio/efeitos dos fármacos , Endotélio/fisiopatologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Hidrazinas/farmacologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/irrigação sanguínea , Camundongos Endogâmicos BALB C , Proteínas dos Microfilamentos/metabolismo , Metástase Neoplásica , Óxido Nítrico/farmacologia , Compostos Nitrosos/uso terapêutico , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Fatores de Tempo
5.
ChemMedChem ; 10(1): 62-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25420874

RESUMO

Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho-, meta-, C,C'-dimethyl meta- and para-carborane clusters. The boronicaine derivatives were tested for their analgesic activity and compared with lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho-carborane = C,C'-dimethyl meta-carborane > para-carborane > lidocaine > meta-carborane derivative. Both ortho-boronicaine and C,C'-dimethyl meta-boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics.


Assuntos
Anestésicos Locais/química , Boranos/química , Anestésicos Locais/síntese química , Anestésicos Locais/uso terapêutico , Animais , Área Sob a Curva , Sítios de Ligação , Boranos/síntese química , Boranos/uso terapêutico , Catálise , Domínio Catalítico , Humanos , Isomerismo , Lidocaína/química , Camundongos , Simulação de Acoplamento Molecular , Dor/tratamento farmacológico , Paládio/química , Curva ROC , Albumina Sérica/química , Albumina Sérica/metabolismo
6.
Proc Natl Acad Sci U S A ; 110(16): 6512-7, 2013 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-23536304

RESUMO

The application of boron neutron capture therapy (BNCT) following liposomal delivery of a (10)B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine and incorporating Na3[1-(2'-B10H9)-2-NH3B10H8] in the aqueous interior and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h--with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)--following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 10(12) neutrons per cm(2) (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study.


Assuntos
Adenocarcinoma/terapia , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Mamárias Experimentais/terapia , Fosfatidilcolinas/uso terapêutico , Animais , Boranos/uso terapêutico , Feminino , Estimativa de Kaplan-Meier , Lipossomos/metabolismo , Lipossomos/uso terapêutico , Camundongos , Fosfatidilcolinas/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
7.
Clin Exp Immunol ; 167(2): 179-87, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22235993

RESUMO

Carbon monoxide (CO) is produced during the catabolism of free haem, catalyzed by haem oxygenase (HO) enzymes, and its physiological roles include vasodilation, neurotransmission, inhibition of platelet aggregation and anti-proliferative effects on smooth muscle. In vivo preclinical studies have shown that exogenously administered quantities of CO may represent an effective treatment for conditions characterized by a dysregulated immune response. The carbon monoxide-releasing molecules (CORMs) represent a group of compounds capable of carrying and liberating controlled quantities of CO in the cellular systems. This review covers the physiological and anti-inflammatory properties of the HO/CO pathway in the central nervous system. It also discusses the effects of CORMs in preclinical models of inflammation. The accumulating data discussed herein support the possibility that CORMs may represent a novel class of drugs with disease-modifying properties in multiple sclerosis.


Assuntos
Boranos/uso terapêutico , Monóxido de Carbono/uso terapêutico , Carbonatos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Autoimunidade/efeitos dos fármacos , Boranos/administração & dosagem , Monóxido de Carbono/administração & dosagem , Monóxido de Carbono/metabolismo , Carbonatos/administração & dosagem , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Citocinas/biossíntese , Avaliação Pré-Clínica de Medicamentos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Guanilato Ciclase/metabolismo , Heme/metabolismo , Heme Oxigenase (Desciclizante)/fisiologia , Heme Oxigenase-1/deficiência , Heme Oxigenase-1/fisiologia , Humanos , Inflamação/tratamento farmacológico , Esclerose Múltipla/imunologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Compostos Organometálicos/administração & dosagem , Oxirredução , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Guanilil Ciclase Solúvel , Vasodilatadores/administração & dosagem , Vasodilatadores/uso terapêutico
8.
J Pharm Sci ; 101(1): 223-32, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21918989

RESUMO

This paper investigates the physicochemical properties of possible pharmaceutical alternatives to L-p-boronphenylalanine (BPA)-fructose intravenous formulation currently employed in boron neutron capture therapy. The physicochemical properties of BPA in the absence and presence of fructose, mannitol, trehalose and hydroxypropyl-ß-cyclodextrin (HPCD) was investigated by determination of pKa values, solubility, precipitation and dissolution using a Sirius T3 instrument. Complex formation was also assessed using (10) B-Nuclear magnetic resonance (NMR). The results indicate that fructose and mannitol form a complex with BPA through a reversible interaction with the boronic acid group, determined by changes in the pKa of the boronic acid group, the ultraviolet and NMR spectra, and increase in kinetic solubility. Trehalose and HPCD did not undergo this reaction and, consequently, did not affect boronphenylalanaine physicochemical properties. Although mannitol is complexed with BPA in an identical manner to fructose, it is superior because it provides increased kinetic solubility. Replacement of fructose by mannitol in the current clinical BPA formulation is, therefore, feasible with advantages of increased dosing and removal of issues related to fructose intolerance and calorific load. Results also indicated that important pharmaceutical parameters are the complex's solubility and dissociation behaviours rather than, as originally assumed, the complex formation reaction.


Assuntos
Boranos/química , Frutose/química , Fenilalanina/análogos & derivados , 2-Hidroxipropil-beta-Ciclodextrina , Boranos/uso terapêutico , Terapia por Captura de Nêutron de Boro/métodos , Ácidos Borônicos/química , Precipitação Química , Química Farmacêutica/métodos , Excipientes/química , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Manitol/química , Farmacocinética , Fenilalanina/química , Fenilalanina/uso terapêutico , Solubilidade , Trealose/química , beta-Ciclodextrinas/química
9.
J Nanosci Nanotechnol ; 11(4): 3091-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21776675

RESUMO

In this report, we describe the effect of conjugating o-carborane-C(1)C(2)-dicarboxylic acid (o-C2B10H10-C2O4H2, denoted as Cbac2) to cadmium telluride quantum dots (CdTe QDs) capped with cysteamine on the photophysics and cytotoxicity of the QDs. Cbac2 quenches the fluorescence intensity and induces a red shift of the fluorescence emission peak. Meanwhile, studies with a real time cell electronic sensing (RT-CES) system and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay indicate that the combination of the carborane carboxylic acid derivative Cbac2 with relevant QDs can efficiently improve the inhibition efficiency for target cancer cells when compared with a single ligand or the CdTe QDs alone. This study raises the possibility for the labeling of the important pharmacophore with QDs and the design of new promising anticancer agents containing the carborane pharmacophores for cancer therapy.


Assuntos
Boranos/uso terapêutico , Compostos de Cádmio/química , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Microscopia de Fluorescência/métodos , Nanocápsulas/química , Pontos Quânticos , Telúrio/química , Linhagem Celular Tumoral , Cor , Humanos , Iluminação/instrumentação
10.
Clin Exp Immunol ; 163(3): 368-74, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21235533

RESUMO

We have evaluated the effects of the carbon monoxide-releasing molecule CORM-A1 [Na(2) (BH(3) CO(2) ); ALF421] on the development of relapsing-remitting experimental allergic encephalomyelitis (EAE) in SJL mice, an established model of multiple sclerosis (MS). The data show that the prolonged prophylactic administration of CORM-A1 improves the clinical and histopathological signs of EAE, as shown by a reduced cumulative score, shorter duration and a lower cumulative incidence of the disease as well as milder inflammatory infiltrations of the spinal cords. This study suggests that the use of CORM-A1 might represent a novel therapeutic strategy for the treatment of multiple sclerosis.


Assuntos
Boranos/uso terapêutico , Monóxido de Carbono/uso terapêutico , Carbonatos/uso terapêutico , Encefalomielite Autoimune Experimental/prevenção & controle , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Peso Corporal/efeitos dos fármacos , Boranos/farmacocinética , Monóxido de Carbono/administração & dosagem , Monóxido de Carbono/sangue , Monóxido de Carbono/farmacologia , Carbonatos/farmacocinética , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos , Neutrófilos/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia
11.
Bioconjug Chem ; 21(12): 2213-21, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21087014

RESUMO

Potential boron neutron capture therapy (BNCT) agents have been designed on the basis of the evidence about translocator protein (TSPO) overexpression on the outer mitochondrial membrane of tumor cells. The structure of the first TSPO ligand bearing a carborane cage (compound 2d) has been modified in order to find a suitable candidate for in vivo studies. The designed compounds were synthesized and evaluated for their potential interaction with TSPO and tumor cells. In vitro biological evaluation showed in the case of fluoromethyl derivative 4b a nanomolar TSPO affinity very similar to that of 2d, a significantly lower cytotoxicity, and a slightly superior performance as boron carrier toward breast cancer cells. Moreover, compound 4b could be used as a ¹9F magnetic resonance imaging (MRI) agent as well as labeled with ¹¹C or ¹8F to obtain positron emission tomography (PET) radiotracers in order to apply the "see and treat" strategy in BNCT.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro , Encéfalo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Mitocôndrias/efeitos dos fármacos , Quinolinas , Receptores de GABA-A/metabolismo , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Animais , Sítios de Ligação , Boranos/síntese química , Boranos/farmacologia , Boranos/uso terapêutico , Boro/química , Boro/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Proteínas de Transporte/química , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Neoplasias do Colo/radioterapia , Cristalografia por Raios X , Feminino , Radioisótopos de Flúor , Expressão Gênica , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Modelos Moleculares , Tomografia por Emissão de Pósitrons , Ligação Proteica , Quinolinas/síntese química , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos , Receptores de GABA-A/química , Receptores de GABA-A/genética , Relação Estrutura-Atividade
12.
Bioconjug Chem ; 19(9): 1796-802, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18712900

RESUMO

Despite the improvements in cancer therapy during the past years, high-grade gliomas and many other types of cancer are still extremely resistant to current forms of therapy. Boron neutron capture therapy (BNCT) provides a promising way to destroy cancer cells without damaging healthy tissue. However, BNCT in practice is still limited due to the lack of boron-containing compounds that selectively deliver boron to cancer cells. Since many neuroendocrine tumors show an overexpression of the somatostatin receptor, it was our aim to synthesize compounds that contain a large number of boron atoms and still show high affinity toward this transmembrane receptor. The synthetic peptide Tyr (3)-octreotate (TATE) was chosen as a high-affinity and internalizing tumor targeting vector (TTV). Novel boron cluster compounds, containing 10 or 20 boron atoms, were coupled to the N-terminus of TATE. The obtained affinity data demonstrate that the use of a spacer between TATE and the closo-borane moiety is the option to avoid a loss of biological affinity of closo-borane conjugated TATE. For the first time, it was shown that closo-borane conjugated regulatory peptides retain high biological affinity and selectivity toward their transmembrane tumor receptors. The results obtained and the improvement of spacer and boron building block chemistry may stimulate new directions for BNCT.


Assuntos
Boranos/síntese química , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias/radioterapia , Peptídeos Cíclicos/síntese química , Animais , Sítios de Ligação , Boranos/metabolismo , Boranos/uso terapêutico , Células CHO , Linhagem Celular , Membrana Celular/química , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Humanos , Neoplasias/tratamento farmacológico , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/uso terapêutico
13.
Drug News Perspect ; 21(5): 258-66, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18596990

RESUMO

Misfolding and subsequent aggregation of any of a number of proteins leads to the accumulation of amyloid fibrils, which have been associated with a variety of diseases. One such amyloidogenic protein is transthyretin (TTR), a 55-kDa homotetrameric protein found in the blood plasma and cerebrospinal fluid where it binds and transports thyroxine. In humans, the T119M-TTR variant has been shown to be protective against familial amyloid polyneuropathy, a TTR amyloid disease, through kinetic stabilization of the unliganded tetrameric structure. Studies have indicated that a diverse range of small molecules may also bind TTR in the thyroxine-binding pocket and subsequently kinetically stabilize the protein's native conformation in vitro, preventing the misfolding that has been implicated in the progression of several diseases. However, cyclooxygenase inhibition is a common unwanted side effect among such small-molecule kinetic stabilizers. The recent development of transthyretin stabilizers not subject to cyclooxygenase inhibition may prove attractive for the long-term treatment of TTR misfolding diseases in humans. Such compounds are attained by incorporating aromatic carborane icosahedra at strategic points in their structures.


Assuntos
Amiloide/antagonistas & inibidores , Amiloidose/tratamento farmacológico , Boranos/uso terapêutico , Pré-Albumina/metabolismo , Amiloidose/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Sítios de Ligação , Boranos/efeitos adversos , Boranos/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Humanos , Pré-Albumina/química , Conformação Proteica , Dobramento de Proteína , Relação Estrutura-Atividade , Tiroxina/metabolismo
14.
J Dent Res ; 87(2): 148-52, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18218841

RESUMO

AN0128 is a boron-containing compound with antibacterial and anti-inflammatory properties. To test its potential effectiveness in treating periodontal disease, we induced experimental periodontitis in the rat by placing ligatures and assessed the impact of AN0128 and positive and negative controls by micro-CT and histologic measurements. The formation of an inflammatory infiltrate was measured in hematoxylin-and-eosin-stained sections. Daily application of AN0128 (1%) compared with controls reduced bone loss by 38 to 44% (P < 0.05), while vehicle alone had no effect (P > 0.05). The reduction in bone loss with AN0128 was similar to that achieved with a NSAID, ketorolac, and Total toothpaste containing triclosan. AN0128 also reduced the level of gingival inflammation 42% compared with the ligature only (P < 0.05), whereas vehicle alone had no effect (P > 0.05). The results indicate that AN0128 significantly reduces the formation of an inflammatory infiltrate and reduces bone loss, measured histologically and by micro-CT.


Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Boranos/uso terapêutico , Periodontite/prevenção & controle , Piridinas/uso terapêutico , Perda do Osso Alveolar/patologia , Perda do Osso Alveolar/prevenção & controle , Animais , Anti-Infecciosos Locais/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Corantes , Misturas Complexas/uso terapêutico , Dentifrícios/uso terapêutico , Etilenoglicóis , Corantes Fluorescentes , Fluoretos/uso terapêutico , Gengivite/patologia , Gengivite/prevenção & controle , Cetorolaco/uso terapêutico , Masculino , Periodontite/patologia , Veículos Farmacêuticos , Ratos , Ratos Sprague-Dawley , Ácido Silícico , Tomografia Computadorizada por Raios X/métodos , Cremes Dentais , Triclosan/uso terapêutico
15.
Dalton Trans ; (38): 4240-51, 2007 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-17893811

RESUMO

The role of carboranes in medicinal chemistry has diversified in recent years and now extends into areas of drug discovery, molecular imaging, and targeted radionuclide therapy. An introduction to carborane chemistry is provided to familiarize the non-expert with some key properties of these molecules, followed by an overview of current medicinally-orientated research involving carboranes. The broad-ranging nature of this research is illustrated, with emphasis placed on recent highlights and advances in this field.


Assuntos
Boranos/química , Boranos/farmacologia , Amiloide/antagonistas & inibidores , Amiloide/metabolismo , Boranos/uso terapêutico , Diagnóstico por Imagem , Desenho de Fármacos , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Receptores de Estrogênio/agonistas , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo
16.
Am J Physiol Heart Circ Physiol ; 293(4): H2501-7, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17630349

RESUMO

Endogenous CO, a product of heme oxygenase activity, has vasodilator and cytoprotective effects in the cerebral circulation of newborn pigs. CO-releasing molecule (CORM)-A1 (sodium boranocarbonate) is a novel, water-soluble, CO-releasing compound. We addressed the hypotheses that CORM-A1 1) can deliver CO to the brain and exert effects of CO on the cerebral microvasculature and 2) is cerebroprotective. Acute and delayed effects of topically and systemically administered CORM-A1 on cerebrovascular and systemic circulatory parameters were determined in anesthetized newborn pigs with implanted closed cranial windows. Topical application of CORM-A1 (10(-7)-10(-5) M) to the brain produced concentration-dependent CO release and pial arteriolar dilation. Systemically administered CORM-A1 (2 mg/kg ip or iv) caused pial arteriolar dilation and increased cortical cerebrospinal fluid CO concentration. Systemic CORM-A1 did not have acute or delayed effects on blood pressure, heart rate, or blood gases. Potential cerebroprotective vascular effects of CORM-A1 (2 mg/kg ip, 30 min before seizures) were tested 2 days after bicuculline-induced epileptic seizures (late postictal period). In control piglets, seizures reduced postictal cerebrovascular responsiveness to selective physiologically relevant vasodilators (bradykinin, hemin, and isoproterenol) indicative of cerebrovascular injury. In contrast, in CORM-A1-pretreated animals, no loss of postictal cerebrovascular reactivity was observed. We conclude that systemically administered CORM-A1 delivers CO to the brain, elicits the vasodilator and cytoprotective effects of CO in the cerebral circulation, and protects the neonatal brain from cerebrovascular injury caused by epileptic seizures.


Assuntos
Boranos/farmacologia , Monóxido de Carbono/metabolismo , Carbonatos/farmacologia , Artérias Cerebrais/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/prevenção & controle , Substâncias Protetoras/farmacologia , Convulsões/complicações , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Administração Tópica , Animais , Animais Recém-Nascidos , Bicuculina , Pressão Sanguínea/efeitos dos fármacos , Boranos/uso terapêutico , Bradicinina/metabolismo , Carbonatos/uso terapêutico , Artérias Cerebrais/metabolismo , Artérias Cerebrais/fisiopatologia , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Hemina/farmacologia , Injeções Intraperitoneais , Injeções Intravenosas , Isoproterenol/farmacologia , Nitroprussiato/farmacologia , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/fisiopatologia , Suínos , Vasodilatadores/administração & dosagem , Vasodilatadores/metabolismo , Vasodilatadores/uso terapêutico
17.
Biophys Chem ; 125(2-3): 320-7, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17079068

RESUMO

The physico-chemical properties of beta-lactosyl-closo-orthocarborane in water solution were investigated by multinuclear NMR, (13)C NMR relaxation, and ab-initio calculations. This molecule represents a potentially selective boron carrier in Boron Neutron Cancer Therapy (BNCT) and exhibits amphiphilic characteristics. Its structural and dynamic features were studied comparing NMR data acquired in both aggregating and non-aggregating conditions. Aggregates are characterized by rapid exchange with the bulk and by high sensitivity to temperature conditions. An unusually stable intra-molecular CH...O hydrogen bond was found to persist in water solution both for the free molecules and after aggregate formation. At the same time, inter-molecular specific CH()O interactions do not seem effective in the aggregate formation process, which appears to take place only on non-specific hydrophobic basis.


Assuntos
Boranos/química , Terapia por Captura de Nêutron de Boro/métodos , Espectroscopia de Ressonância Magnética/métodos , Boranos/uso terapêutico , Carboidratos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Soluções/química , Tensoativos , Temperatura
18.
Anticancer Agents Med Chem ; 6(2): 75-109, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16529534

RESUMO

The use of polyhedral boron hydrides for cancer treatment is traditionally connected with boron neutron capture therapy. More recently, polyhedral borate anions were proposed as carriers of radionuclide label for targeted radionuclide therapy and diagnostics of cancer. Some metal derivatives of carboranes were found to demonstrate significant antitumor activity themselves. This review is designed to highlight the recent work concerning various fields of potential application of polyhedral boron compounds in anticancer diagnostics and therapy.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Boro/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Animais , Boranos/farmacocinética , Boranos/uso terapêutico , Terapia por Captura de Nêutron de Boro/métodos , Linhagem Celular Tumoral , Humanos , Neoplasias/radioterapia
19.
Anticancer Agents Med Chem ; 6(2): 127-44, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16529536

RESUMO

One category of boron neutron capture therapy (BNCT) agents that has received extensive attention during recent years is 3-carboranyl thymidine analogues (3CTAs). These molecules are phosphorylated to the corresponding 5'-monophosphates by human thymidine kinase 1 (TK1), an enzyme that is up-regulated in dividing malignant cells. Thus, these phosphorylated molecules are selectively entrapped in tumor cells due to the acquired negative charge. This review will analyze design strategies applied for the synthesis of boron-containing nucleosides in general and in particular reference to 3CTAs. Results of biological studies with these molecules will be discussed.


Assuntos
Boranos/síntese química , Terapia por Captura de Nêutron de Boro/métodos , Nucleosídeos/síntese química , Timidina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Boranos/uso terapêutico , Humanos , Nucleosídeos/uso terapêutico , Nucleotídeos/síntese química , Nucleotídeos/uso terapêutico , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/uso terapêutico , Timidina/síntese química , Timidina Quinase/metabolismo
20.
Expert Opin Investig Drugs ; 14(11): 1305-18, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16255672

RESUMO

Carbon monoxide (CO), which is formed in mammalian cells through the oxidation of haem by the enzyme haem oxygenase, actively participates in the regulation of key intracellular functions. Emerging evidence reveals that an increased generation of haem oxygenase-derived CO plays a critical role in the resolution of inflammatory processes and alleviation of cardiovascular disorders. The authors have identified a novel class of substances, CO-releasing molecules (CO-RMs), which are capable of exerting a variety of pharmacological activities via the liberation of controlled amounts of CO in biological systems. A wide range of CO carriers containing manganese (CORM-1), ruthenium (CORM-2 and -3), boron (CORM-A1) and iron (CORM-F3) are currently being investigated to tailor therapeutic approaches for the prevention of vascular dysfunction, inflammation, tissue ischaemia and organ rejection.


Assuntos
Boranos/uso terapêutico , Monóxido de Carbono/metabolismo , Carbonatos/uso terapêutico , Compostos Organometálicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Boranos/farmacologia , Carbonatos/farmacologia , Heme Oxigenase-1/fisiologia , Humanos , Nefropatias/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Compostos Organometálicos/farmacologia
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