Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Oncotarget ; 11(46): 4281-4292, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33245733

RESUMO

PURPOSE: 12b80 combines doxorubicin bound to a bone targeting hydroxybisphosphonate vector using a pH-sensitive linker, designed to specifically trigger doxorubicin release in an acidic bone tumor microenvironment. This phase I study aimed to determine the safety and toxicity profiles of 12b80 in dogs with naturally occurring osteosarcoma, with the objective to translate findings from dogs to humans. EXPERIMENTAL DESIGN: Ten client-owned dogs with osteosarcoma were enrolled in an accelerated dose-titration design followed by 3 + 3 design. Dogs received three cycles of 12b80 intravenous injection at 4 mg/kg (n = 1), 6 mg/kg (n = 2), 8 mg/kg (n = 3), and 10 mg/kg (n = 4). Endpoints included safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT). RESULTS: The MTD of 12b80 was 8 mg/kg (i.e., equivalent dose of doxorubicin of 110 mg/m2, range: 93-126). Most adverse events included grade ≤ 2 gastrointestinal disorders and hypersensitivity reactions. No hematological or cardiac DLT were observed at any dose tested. CONCLUSIONS: In dogs, 12b80 is overall well tolerated and expends the MTD of doxorubicin up to four times the standard dose of 30 mg/m2. These results demonstrate the potential therapeutic benefit of 12b80 in canine and human osteosarcoma.

2.
Bioconjug Chem ; 30(6): 1665-1676, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31045351

RESUMO

To reply to as yet unmet medical needs to treat osteosarcoma, a form of primary bone cancer, we conceived the 12b80 compound by covalently conjugating antineoplastic compound doxorubicin to a bone targeting hydroxybisphosphonate vector and turned it into a prodrug through a custom linker designed to specifically trigger doxorubicin release in acidic bone tumor microenvironment. Synthesis of 12b80 was thoroughly optimized to be produced at gram scale. 12b80 was evaluated in vitro for high bone support affinity, specific release of doxorubicin in acidic condition, lower cytotoxicity, and cellular uptake of the prodrug. In vivo in rodents, 12b80 displayed rapid and sustained targeting of bone tissue and tumor-associated heterotopic bone and permitted a higher doxorubicin payload in tumor bone environment compared to nonvectorized doxorubicin. Consequently, 12b80 showed much lower toxicity compared to doxorubicin, promoted strong antitumor effects on rodent orthotopic osteosarcoma, displayed a dose-response therapeutic effect, and was more potent than doxorubicin/zoledronate combination.


Assuntos
Antibióticos Antineoplásicos/química , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/química , Doxorrubicina/análogos & derivados , Osteossarcoma/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Difosfonatos/síntese química , Difosfonatos/farmacocinética , Difosfonatos/uso terapêutico , Doxorrubicina/síntese química , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Feminino , Camundongos Nus , Osteossarcoma/patologia , Ratos
3.
Cancer Res ; 78(18): 5384-5397, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054335

RESUMO

The mTOR is a central regulator of cell growth and is highly activated in cancer cells to allow rapid tumor growth. The use of mTOR inhibitors as anticancer therapy has been approved for some types of tumors, albeit with modest results. We recently reported the synthesis of ICSN3250, a halitulin analogue with enhanced cytotoxicity. We report here that ICSN3250 is a specific mTOR inhibitor that operates through a mechanism distinct from those described for previous mTOR inhibitors. ICSN3250 competed with and displaced phosphatidic acid from the FRB domain in mTOR, thus preventing mTOR activation and leading to cytotoxicity. Docking and molecular dynamics simulations evidenced not only the high conformational plasticity of the FRB domain, but also the specific interactions of both ICSN3250 and phosphatidic acid with the FRB domain in mTOR. Furthermore, ICSN3250 toxicity was shown to act specifically in cancer cells, as noncancer cells showed up to 100-fold less sensitivity to ICSN3250, in contrast to other mTOR inhibitors that did not show selectivity. Thus, our results define ICSN3250 as a new class of mTOR inhibitors that specifically targets cancer cells.Significance: ICSN3250 defines a new class of mTORC1 inhibitors that displaces phosphatidic acid at the FRB domain of mTOR, inducing cell death specifically in cancer cells but not in noncancer cells. Cancer Res; 78(18); 5384-97. ©2018 AACR.


Assuntos
Neoplasias/metabolismo , Ácidos Fosfatídicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Técnicas de Cocultura , Fibroblastos/metabolismo , Células HCT116 , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Células K562 , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/farmacologia
4.
Oxid Med Cell Longev ; 2016: 8703645, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27293517

RESUMO

Rheumatoid arthritis is one of the most common autoimmune diseases. Many antioxidants have been tested in arthritis, but their efficacy was, at best, marginal. In this study, a novel mitochondria-targeted antioxidant, plastoquinonyl-decyl-triphenylphosphonium bromide (SkQ1), was tested in vivo to prevent and cure experimental autoimmune arthritis. In conventional Wistar rats, SkQ1 completely prevented the development of clinical signs of arthritis if administered with food before induction. Further, SkQ1 significantly reduced the fraction of animals that developed clinical signs of arthritis and severity of pathological lesions if administration began immediately after induction of arthritis or at the onset of first symptoms (day 14 after induction). In specific pathogen-free Wistar rats, SkQ1 administered via gavage after induction of arthritis did not reduce the fraction of animals with arthritis but decreased the severity of lesions upon pathology examination in a dose-dependent manner. Efficacious doses of SkQ1 were in the range of 0.25-1.25 nmol/kg/day (0.13-0.7 µg/kg/day), which is much lower than doses commonly used for conventional antioxidants. SkQ1 promoted apoptosis of neutrophils in vitro, which may be one of the mechanisms underlying its pharmacological activity. Considering its low toxicity and the wide therapeutic window, SkQ1 may be a valuable additional therapy for rheumatoid arthritis.


Assuntos
Antioxidantes/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Articulações/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Plastoquinona/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Linhagem Celular , Colágeno Tipo II , Relação Dose-Resposta a Droga , Humanos , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Mitocôndrias/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Plastoquinona/farmacologia , Ratos Wistar , Fatores de Tempo
5.
Eur J Med Chem ; 79: 244-50, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24742383

RESUMO

Ligerin (1) is a natural chlorinated merosesquiterpenoid related to fumagillin (2) exhibiting a selective antiproliferative activity against osteosarcoma cell lines and an in vivo antitumor activity in a murine model. Semisynthesis of ligerin analogs was performed in order to study the effects of the C3-spiroepoxide substitution by a halogenated moiety together with the modulation of the C6 chain. Results showed that all derivatives exhibited an in vitro antiproliferative activity against osteosarcoma cell lines and that chlorohydrin compounds were equally or more active than their spiroepoxy analogs. Among semisynthetic analogs, the parent compound 1 was the best candidate for further studies since it exhibited higher or equivalent activity compared to TNP470 (3) against SaOS2 and MG63 human osteosarcoma cells with a four times weaker toxicity against HFF2 human fibroblasts. Quantitative videomicroscopy analysis was conducted and allowed a better understanding of the mechanism of its antiproliferative activity.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Cicloexanos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Osteossarcoma/tratamento farmacológico , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cicloexanos/síntese química , Cicloexanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Conformação Molecular , Osteossarcoma/patologia , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade
6.
Org Biomol Chem ; 12(9): 1518-24, 2014 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-24448828

RESUMO

A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-aminopropyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration, in a caspase-independent cell death mechanism.


Assuntos
Antineoplásicos/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Células K562 , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
7.
J Nat Prod ; 76(2): 297-301, 2013 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-23360521

RESUMO

A new chlorinated sesquiterpenoid analogue of fumagillin, ligerin (1), was isolated from a marine-derived strain of Penicillium, belonging to the subgenus Penicillium, along with the known compounds penicillic acid (2), orcinol, and orsellinic acid. Chemical structures were established by an interpretation of spectroscopic data including IR, UV, and HRESIMS, together with analyses of 1D and 2D NMR spectra and X-ray analysis for the determination of the absolute configuration. Ligerin (1) displayed strong inhibitory activity against an osteosarcoma cell line. This is the first report of the isolation of a fumagillin analogue from a marine-derived Penicillium strain.


Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Hidrocarbonetos Clorados/isolamento & purificação , Hidrocarbonetos Clorados/farmacologia , Penicillium/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Antineoplásicos/química , Cicloexanos/química , Cicloexanos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Estuários , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/isolamento & purificação , França , Hidrocarbonetos Clorados/química , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Osteossarcoma/tratamento farmacológico , Ácido Penicílico/isolamento & purificação , Sesquiterpenos/química
8.
Aging (Albany NY) ; 3(11): 1110-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22166671

RESUMO

The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. To this end, low pathogen (LP) or specific pathogen free (SPF) vivaria in St. Petersburg, Moscow, and Stockholm were used. For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions. It was found that substitution of a LP vivarium for a conventional (non-LP) one doubled the lifespan of female outbred mice, just as SkQ1 did in a non-LP vivarium. SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice in both LP and non-LP vivaria. In the SPF vivarium in Moscow, male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice housed individually in the SPF vivarium in Stockholm lived as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Longevidade/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Plastoquinona/análogos & derivados , Animais , Arvicolinae , Cricetinae , Feminino , Expectativa de Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Plastoquinona/farmacologia
9.
European J Org Chem ; 2011(36): 7390-7399, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34566488

RESUMO

A set of pyrimidine nucleosides fused with a 4'-C,3'-O-propylene bridge was successfully synthesised in 12 steps from 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose, an inexpensive starting material, based on a ring-closing metathesis (RCM) reaction followed by Vorbrüggen-type nucleobase coupling. Antiviral and cytotoxicity activities of the targeted modified nucleosides, as well as their phosphoramidate prodrugs, are described.

10.
Bioconjug Chem ; 17(6): 1441-6, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17105222

RESUMO

2,2'-Bipyridine (bpy) or 1,10-phenanthroline (phen) metal-binding domains were covalently attached to oligonucleotides, and the influence of metal ions on the hybridization of the conjugates was investigated. Metal-binding domains were attached to oligonucleotides at 3'- and 5'-terminal positions, thus placing them in juxtaposed positions after hybridization to a common target strand. While the ligands alone had a positive effect (increased Tm) on hybrid stability, the duplex was further stabilized by the addition of copper(I) and/or copper(II) through the formation of a metal complex in which the two short sequences are linked through {Cu(bpy)2}, {Cu(phen)}, or {Cu(bpy)(phen)} domains. The increase in Tm, due to formation of the {Cu(bpy)2}, {Cu(phen)2}, {Cu(bpy)(phen)} motifs is reversed upon addition of EDTA, consistent with the stripping of copper from the ligands. The effect of metal complex formation on the duplex strength was shown to be highest if the two metal-coordinating ligand strands are placed as close to each other as possible.


Assuntos
Cobre/química , DNA/química , Ácido Edético , Íons/química , Ligantes , Conformação de Ácido Nucleico , Desnaturação de Ácido Nucleico , Compostos Organofosforados/química , Temperatura
11.
Protein Expr Purif ; 36(1): 31-9, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15177281

RESUMO

A Ca2+ -dependent calmodulin-binding peptide (CBP) is an attractive tag for affinity purification of recombinant proteins, especially membrane proteins, since elution is simply accomplished by removing/chelating Ca2+. To develop a single-step calmodulin/CBP-dependent purification procedure for Escherichia coli nicotinamide nucleotide transhydrogenase, a 49 amino acid large CBP or a larger 149 amino acid C-terminal fragment of human plasma membrane Ca2+ -ATPase (hPMCA) was fused C-terminally to the beta subunit of transhydrogenase. Fusion using the 49 amino acid fragment resulted in a dramatic loss of transhydrogenase expression while fusion with the 149 amino acid fragment gave a satisfactory expression. This chimeric protein was purified by affinity chromatography on calmodulin-Sepharose with mild elution with EDTA. The purity and activity were comparable to those obtained with His-tagged transhydrogenase and showed an increased stability. CBP-tagged transhydrogenase contained a 4- to 10-fold higher amount of the alpha subunit relative to the beta subunit as compared to wild-type transhydrogenase. To determine whether the latter was due to the CBP tag, a double-tagged transhydrogenase with both an N-terminal 6x His-tag and a CBP-tag, purified by using either tag, gave no significant increase in purity as compared to the single-tagged protein. The reasons for the altered subunit composition are discussed. The results suggest that, depending on the construct, the CBP-tag may be a suitable affinity purification tag for membrane proteins in general.


Assuntos
ATPases Transportadoras de Cálcio/genética , Proteínas de Ligação a Calmodulina/genética , Escherichia coli/enzimologia , NADP Trans-Hidrogenases/genética , Sequência de Aminoácidos , ATPases Transportadoras de Cálcio/química , Calmodulina/química , Proteínas de Ligação a Calmodulina/química , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Cromatografia de Afinidade/métodos , Clonagem Molecular , Escherichia coli/química , Vetores Genéticos/genética , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/isolamento & purificação , Dados de Sequência Molecular , NADP Trans-Hidrogenases/química , NADP Trans-Hidrogenases/isolamento & purificação , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/isolamento & purificação , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação
12.
Acta Crystallogr C ; 59(Pt 8): o451-3, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12909775

RESUMO

The conformation of the crystal of 17beta-ethoxy-3-methoxy-8-isoestra-1,3,5(10)-triene, C(21)H(30)O(2), (I), has been established and compared with the molecular structure of a typical steroid estrogen 8-iso-analogue, (II). Calculations of distances separating some of the H-atom pairs in (I) and (II) by molecular-mechanical and semi-empirical methods revealed the similarity of the values to the H.H distances obtained from X-ray analysis.

13.
Artigo em Inglês | MEDLINE | ID: mdl-12223207

RESUMO

Proton-translocating nicotinamide nucleotide transhydrogenase is located in the mitochondrial inner membrane and catalyzes the reduction of NADP(+) by NADH to NADPH and NAD(+). The present investigation describes the expression of the transhydrogenase gene in various mouse organs, subsections of the human brain and Caenorhabditis elegans. In the mouse, the expression was highest in heart tissue (100%) followed by kidney (64%), testis (52%), adrenal gland (41%), liver (35%), pancreas (34%), bladder (26%), lung (25%), ovary (21%) and brain (14%). The expression in brain tissue was further investigated in the human brain which showed a distribution that apparently varied as a function of neuronal density, a result that was supported by estimations of expression in C. elegans using Green Fluorescent Protein (GFP) controlled by the transhydrogenase promoter. GFP-expressing C. elegans lines showed a clear concentration of fluorescence to the gut, the pharyngeal-intestinal valve and certain neurons. It is concluded that the transhydrogenase gene is expressed to various extents in all cell types in mouse, human and C. elegans.


Assuntos
Encéfalo/enzimologia , Caenorhabditis elegans/enzimologia , NADP Trans-Hidrogenases/metabolismo , Animais , Northern Blotting , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans , Feminino , Proteínas de Fluorescência Verde , Humanos , Proteínas Luminescentes/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , NADP Trans-Hidrogenases/genética , Neurônios/enzimologia , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Distribuição Tecidual
14.
Acta Crystallogr C ; 58(Pt 3): o170-1, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11870317

RESUMO

The Birch reduction of 3-methoxy-B-nor-8-isoestra-1,3,5(10)-trienes followed by acid hydrolysis produces steroid androgen 19,B-dinor-8,10-iso-analogues. By means of X-ray analysis and correlation NMR spectroscopy of 16,16-dimethyl-D-homo-19,B-dinor-8-isotestosterone, C(20)H(30)O(2), it is demonstrated that the main conformations in the crystal and in solution for two 19,B-dinor-8,10-iso-analogues are, in general, the same.


Assuntos
Noresteroides/química , Congêneres da Testosterona/síntese química , Testosterona/química , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Testosterona/análogos & derivados
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...