RESUMO
The controlled self-assembly of peptide- and protein-based pharmaceuticals is of central importance for their mode of action and tuning of their properties. Peptide YY3-36 (PYY3-36 ) is a 36-residue peptide hormone that reduces food intake when peripherally administered. Herein, we describe the synthesis of a PYY3-36 analogue functionalized with a metal-ion-binding 2,2'-bipyridine ligand that enables self-assembly through metal complexation. Upon addition of CuII , the bipyridine-modified PYY3-36 peptide binds stoichiometric quantities of metal ions in solution and contributes to the organization of higher-order assemblies. In this study, we aimed to explore the size effect of the self-assembly inâ vivo by using non-invasive quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. For this purpose, bipyridine-modified PYY3-36 was radiolabeled with a chelator holding 111 InIII , followed by the addition of CuII to the bipyridine ligand. SPECT/CT imaging and biodistribution studies showed fast renal clearance and accumulation in the kidney cortex. The radiolabeled bipyridyl-PYY3-36 conjugates with and without CuII presented a slightly slower excretion 1â h post injection compared to the unmodified-PYY3-36 , thus demonstrating that higher self-assemblies of the peptide might have an effect on the pharmacokinetics.
Assuntos
Cobre/farmacocinética , Peptídeo YY/farmacocinética , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacocinética , Animais , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Cobre/química , Feminino , Córtex Renal/química , Córtex Renal/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Peptídeo YY/síntese química , Peptídeo YY/química , Eliminação Renal , Distribuição TecidualRESUMO
Hetero-bimetallic and -trimetallic complexes were synthesized by the combination of different metallic fragments, a luminescent Re(I) species, and a bioactive Au(I) derivative. A ditopic P,N-donor ligand (L) was used as linker between both metals, affording six new bipyridine (bipy) Re(I)/Au(I) hetero-metallic complexes of the type fac-[Re(bipy)(CO)3(LAuCl)]+ (4-6) and [(fac-[Re(bipy)(CO)3(L)])2Au]3+ (7-9) after a thorough synthetic procedure. Their emission is associated with a triplet metal-to-ligand charge transfer (Re(dπ) â bipy(π*)) transition and red-shifted in polar solvents with lifetimes in the range of nanoseconds and quantum yield values up to 12.5%. Cytotoxicity values in A549 cells of hetero-trimetallic species are almost twice that for the hetero-bimetallic (ca. 37 vs 69 µM, respectively), being the L-Au fragment the source of the antiproliferative activity. Species 7 and 8 showed similar behavior by fluorescence microscopy, with a nonuniform cytoplasmatic distribution, a clear accumulation in single spots at the edge of the inner cell membrane as well as in areas within the nucleus. Preliminary studies suggest the DNA as one of the targets and passive diffusion as the entrance pathway.
Assuntos
2,2'-Dipiridil/química , Antineoplásicos/química , Complexos de Coordenação/química , Ouro/química , Substâncias Luminescentes/química , Rênio/química , 2,2'-Dipiridil/farmacocinética , 2,2'-Dipiridil/farmacologia , Células A549 , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Ouro/farmacocinética , Ouro/farmacologia , Humanos , Ligantes , Luminescência , Substâncias Luminescentes/farmacocinética , Substâncias Luminescentes/farmacologia , Neoplasias/tratamento farmacológico , Imagem Óptica , Rênio/farmacocinética , Rênio/farmacologiaRESUMO
Mesoporous silica nanoparticles (MSNs) were co-doped with Gd(3+) and Al(3+) and then loaded with Ru(bpy)3(2+) by ion-exchange to prepare Ru/Gd-Al@MSNs. The as-prepared Ru/Gd-Al@MSNs were applied as contrast agents for in vivo fluorescence and magnetic resonance (MR) dual-modality imaging with a mouse as a model. The effects of Al(3+) and MSNs on longitudinal relaxivity (r1) and fluorescence were investigated using a series of Gd-containing silica nanoparticles, including Gd@MSNs, Gd-Al@MSNs, and Ru/Gd-Al@nonporous silica nanoparticles. Co-doping with Al(3+) improved the loading of Gd(3+); the mesoporous structure improved the water exchange rate. The improvement enhanced the MR imaging efficiency of the Ru/Gd-Al@MSN probe. A higher relaxivity (19.2 mM(-1) s(-1)) was observed compared to that from a commercial contrast agent, Gd-diethylene triamine pentaacetic acid (Gd-DTPA). Importantly, the mesoporous structure provided a large specific surface area for the loading of Ru(bpy)3(2+) by a simple ion-exchange procedure. Intense red fluorescence was observed from Ru/Gd-Al@MSN probes. The versatility of Ru/Gd-Al@MSNs for dual-modality imaging was demonstrated using in vivo fluorescence imaging and T1-weighted MR imaging with a mouse model. The nanoparticles are biocompatible and may be attractive for clinical applications.
Assuntos
2,2'-Dipiridil/análogos & derivados , Alumínio/administração & dosagem , Meios de Contraste/administração & dosagem , Corantes Fluorescentes/administração & dosagem , Gadolínio/administração & dosagem , Nanopartículas/química , Dióxido de Silício/química , 2,2'-Dipiridil/administração & dosagem , 2,2'-Dipiridil/farmacocinética , Alumínio/farmacocinética , Animais , Meios de Contraste/farmacocinética , Complexos de Coordenação , Feminino , Corantes Fluorescentes/farmacocinética , Gadolínio/farmacocinética , Gadolínio DTPA/administração & dosagem , Gadolínio DTPA/farmacocinética , Células Hep G2 , Humanos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Nanopartículas/ultraestrutura , Imagem Óptica , PorosidadeRESUMO
The water-soluble rhenium(I) complex fac-[Re(bpy)(CO)(3)(thp)](+) (1) [CF(3)SO(3)(-) salt; bpy = 2,2'-bipyridine, thp = tris(hydroxymethyl)phosphine] is both strongly luminescent and photoactive toward carbon monoxide release. It is stable in aerated aqueous media, is incorporated into cells from the human prostatic carcinoma cell line PPC-1, and shows no apparent cytotoxicity. Furthermore, the solvated Re(I) photoproduct of CO release (2) is also luminescent, a feature that allows one to track the transformation of 1 to 2 inside such cells using confocal fluorescence microscopy. In this context, 1 is a very promising candidate as a photoactivated CO releasing moiety (photoCORM) with potential therapeutic applications.
Assuntos
2,2'-Dipiridil/química , Monóxido de Carbono/administração & dosagem , Substâncias Luminescentes/química , Fosfinas/química , Rênio/química , 2,2'-Dipiridil/farmacocinética , 2,2'-Dipiridil/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/toxicidade , Humanos , Luminescência , Substâncias Luminescentes/farmacocinética , Substâncias Luminescentes/toxicidade , Fosfinas/farmacocinética , Fosfinas/toxicidade , Processos Fotoquímicos , Rênio/farmacocinética , Rênio/toxicidadeRESUMO
This manuscript describes cell-uptake studies with HEK 293T cells on a series of ruthenium complexes shown previously to act as receptors for protein surface recognition and was motivated by a desire to establish if these receptors represent suitable templates for further elaboration as inhibitors of protein-protein interactions. The results illustrate that large (>3000Da) highly functionalized anionic ruthenium complexes are efficiently transfected via endocytosis to lysosomes with negligible toxicity.
Assuntos
2,2'-Dipiridil/análogos & derivados , Mimetismo Molecular/efeitos dos fármacos , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação , Relação Dose-Resposta a Droga , Endocitose/efeitos dos fármacos , Células HEK293 , Humanos , Lisossomos/efeitos dos fármacos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
Orellanine is a nephrotoxin found in mushrooms of the Cortinarius family. Accidental intake of this substance may cause renal failure. Orellanine is specific for proximal tubular cells and could, therefore, potentially be used as treatment for metastatic renal cancer, which originates from these cells. However, more information is needed about the distribution and elimination of orellanine from the body to understand its potential use for therapy. In this study, 5 mg/kg orellanine (unlabeled and ³H-labeled) was injected intravenously in rats (Wistar and Sprague Dawley). Distribution was measured (Wistar rats, n = 10, n = 12) using radioluminography and the highest amount of orellanine was found in the kidney cortex and bladder at all time-points investigated. The pharmacokinetic properties of orellanine was investigated using LC-MS/MS and ß-scintillation to measure the amount of orellanine in plasma. Three groups of rats were investigated: control rats with intact kidneys (n = 10) and two groups with bilateral renal artery ligation (n = 7) where animals in one of these groups were treated with peritoneal dialysis (n = 8). Using LC-MS/MS, the half-life of orellanine was found to be 109 ± 6 min in the controls. In the groups with ligated renal arteries, orellanine had a half-life of 756 ± 98 min without and 238 ± 28 min with dialysis. Thus, orellanine was almost exclusively eliminated by glomerular filtration as well as by peritoneal dialysis.
Assuntos
2,2'-Dipiridil/análogos & derivados , Micotoxinas/farmacocinética , 2,2'-Dipiridil/farmacocinética , Animais , Rim/fisiologia , Masculino , Micotoxinas/sangue , Ratos Sprague-Dawley , Ratos Wistar , Diálise RenalRESUMO
Orellanine is a nephrotoxic toxin produced by some mushroom species of the Cortinarius genus, typically found in Europe and North America. The nephrotoxicity of Cortinarius orellanus is well known and was first recognized in the 1950s when this mushroom was identified as the cause of a mass poisoning in Poland. Typically, onset of symptoms is delayed for 1-2 weeks after ingestion. Some patients suffer mild gastrointestinal discomfort in the latency period before developing signs of renal impairment due to severe interstitial nephritis, acute focal tubular damage, and interstitial fibrosis. There is no specific antidote to orellanine poisoning. The mainstay of treatment is the prevention of secondary complications of kidney failure, adequate dialysis and, in the case of incomplete recovery, management of chronic renal insufficiency. : In this work, we aim to review about Cortinarius species, including epidemiological studies, chemical structure, toxicokinetics, toxic doses, mechanisms of toxicity, diagnosis, prognosis, and treatment options.
Assuntos
2,2'-Dipiridil/análogos & derivados , Cortinarius/química , Intoxicação Alimentar por Cogumelos/epidemiologia , Micotoxinas/toxicidade , 2,2'-Dipiridil/química , 2,2'-Dipiridil/isolamento & purificação , 2,2'-Dipiridil/farmacocinética , 2,2'-Dipiridil/toxicidade , Animais , Cortinarius/crescimento & desenvolvimento , Humanos , Dose Letal Mediana , Estrutura Molecular , Intoxicação Alimentar por Cogumelos/complicações , Intoxicação Alimentar por Cogumelos/diagnóstico , Intoxicação Alimentar por Cogumelos/terapia , Micotoxinas/química , Micotoxinas/isolamento & purificação , Micotoxinas/farmacocinética , Insuficiência Renal/epidemiologia , Insuficiência Renal/etiologia , ToxicocinéticaRESUMO
[reaction: see text] Bright green boradiazaindacene fluorescence is quenched by an oxidative photoinduced electron transfer (PET) from the excited state fluorophore to the bipyridyl unit complexed to metal cations. The closed shell diamagnetic cation Zn(II) is one of the most effective quenchers of fluorescence in this system, demonstrating that the quenching is not simply related to the facilitated intersystem crossing. The molecule also acts as a NOR logic gate with two chemical inputs, TFA and Zn(II).
Assuntos
2,2'-Dipiridil/síntese química , Compostos Aza/síntese química , Boranos/síntese química , Corantes Fluorescentes/síntese química , Zinco/análise , 2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacocinética , Compostos Aza/química , Compostos Aza/farmacocinética , Boranos/química , Boranos/farmacocinética , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacocinética , Cátions/análise , Cátions/química , Cátions/farmacologia , Quelantes/síntese química , Quelantes/química , Quelantes/farmacocinética , Elétrons , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Oxirredução , Fotoquímica , Zinco/química , Zinco/farmacologiaRESUMO
The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.
Assuntos
2,2'-Dipiridil/análogos & derivados , Aminopiridinas/síntese química , Naftiridinas/síntese química , Piperazinas/síntese química , Proteína Quinase C/antagonistas & inibidores , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/farmacocinética , 2,2'-Dipiridil/farmacologia , Transporte Ativo do Núcleo Celular , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Histona Desacetilases/metabolismo , Isoenzimas/antagonistas & inibidores , Masculino , Modelos Moleculares , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Células Musculares/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Fosforilação , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A new strategy to build caged-compounds is presented. The approach is based on heterolytic photocleavage of a metal-ligand bond in a coordination compound. A ruthenium polypyridine complex, containing the neurocompound 4-amino pyridine (4AP) is used as the core of the phototrigger. The biomolecule is released by irradiation with visible light (>480 nm). The liberated 4AP promotes the activation of a leech neuron by means of blocking its K+ channels. The syntesis, characterization, and the inherent advantages of this method are discussed.