RESUMO
Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, 2) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, 1), we performed a systematic study on the oxidation of CBD (1) to CBDQ (2) under a variety of experimental conditions (base-catalyzed aerobic oxidation, oxidation with metals, oxidation with hypervalent iodine reagents). The best results in terms of reproducibility and scalability were obtained with λ5-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ5,2-benziodoxole-1,3-dione (IBX), and SIBX, a stabilized, nonexplosive version of IBX). With these reagents, the oxidative dimerization that plagues the reaction under basic aerobic conditions was completely suppressed. A different reaction course was observed with the copper(II) chloride-hydroxylamine complex (Takehira reagent), which afforded a mixture of the hydroxyiminodienone 11 and the halogenated resorcinol 12. The λ5-periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, 18), cannabichromene (CBC, 10), and cannabinol (CBN, 19) into their corresponding hydroxyquinones (20, 21, and 22, respectively). All cannabinoquinoids modulated to a various extent peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, outperforming their parent resorcinols in terms of potency, but the iminoquinone 11, the quinone dimers 3 and 23, and the haloresorcinol 12 were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.
Assuntos
Canabidiol/química , Canabinoides/química , Canabinoides/síntese química , PPAR gama/química , Quinonas/química , Oxirredução , Reprodutibilidade dos Testes , Resorcinóis/químicaRESUMO
Two structurally constrained chelators based on a fused bicyclic scaffold, 4-amino-4-methylperhydro-pyrido[1,2-a][1,4]diazepin-N,N',N'-triacetic acids [(4R*,10aS*)-PIDAZTA (L1) and (4R*,10aR*)-PIDAZTA (L2)], were designed for the preparation of GaIII -based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected [Ga(L2)OH] species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of GaIII into the cavity of L2. Fast and efficient formation of the GaIII chelates at room temperature was observed at pH values between 7 and 8, which enables 68 Ga radiolabeling under truly physiological conditions (pHâ 7.4).
Assuntos
Compostos Bicíclicos com Pontes/química , Quelantes/química , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Teoria da Densidade Funcional , Radioisótopos de Gálio/química , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Cinética , Conformação Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Transferrina/químicaRESUMO
Perimidines are a particularly versatile family of heterocyclic compounds, whose properties are exploited in several applications ranging from industrial to medicinal chemistry. The molecular structure of perimidine incorporates a well-known efficient fluorophore, i.e.: 1,8-diaminonaphthalene. The high fluorescence quantum yield shared by most naphthalene derivatives, has enabled their use as stains for bio-imaging and biophysical characterizations. However, fluorescence is dramatically depressed in perimidine as well as in the few of its derivatives analysed so far to this respect. The use of perimidine-like molecules in life sciences might be notably fostered by enhancement of their fluorescence emission. Even more excitingly, the concomitance of both biologically active moieties and a fluorophore in the same molecular structure virtually discloses application of perimidines as drug compounds in state-of-art theranostics protocols. However, somewhat surprisingly, relatively few attempts were made until now in the direction of increasing the performances of perimidines as fluorescent dyes. In this work we present the synthesis and spectroscopic characterization of four perimidine derivatives designed to this aim, two of which result to be endowed with fluorescence quantum yields comparable to 1,8-diaminonaphthalene. A rationalization for such improved behaviour has been attempted employing TD-DFT calculations, which have unravelled the interrelations among bond structure, lone pair conjugation, local electron density changes and fluorescence quantum yield.
RESUMO
Unprecedented fast and efficient complexation of ScIII was demonstrated with the chelating agent AAZTA (AAZTA=1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) under mild experimental conditions. The robustness of the 44 Sc(AAZTA)- chelate and conjugated biomolecules thereof is further shown by inâ vivo PET imaging in healthy and tumor mice models. The new results pave the way towards development of efficient Sc-based radiopharmaceuticals using the AAZTA chelator.
RESUMO
N-Substituted aminoethyl groups were attached to 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) with the aim to design pH-responsive Ln(III) complexes based on the pH-dependent on/off ligation of the amine nitrogen to the metal ion. The following ligands were synthesized: AE-DO3A (aminoethyl-DO3A), MAE-DO3A (N-methylaminoethyl-DO3A), DMAE-DO3A (N,N-dimethylaminoethyl-DO3A) and MEM-AE-DO3A (N-methoxyethyl-N-methylaminoethyl-DO3A). The physicochemical properties of the Ln(III) complexes were investigated for the evaluation of their potential applicability as magnetic resonance imaging (MRI) contrast agents. In particular, a (1) H and (17) Oâ NMR relaxometric study was carried out for these Gd(III) complexes at two different pH values: at basic pH (pendant amino group coordinated to the metal centre) and at acidic pH (protonated amine, not interacting with the metal ion). Eu(III) complexes allow one to estimate the number of inner-sphere water molecules through luminescence lifetime measurements and obtain some structural information through variable-temperature (VT) high-resolution (1) Hâ NMR studies. Equilibria between differently hydrated species were found for most of the complexes at both acidic and basic pH. The thermodynamic stability of Ca(II) , Zn(II) , Cu(II) and Ln(III) complexes and kinetics of formation and dissociation reactions of Ln(III) complexes of AE-DO3A and DMAE-DO3A were investigated showing stabilities comparable to currently approved Gd(III) -based CAs. In detail, higher total basicity (Σlog Ki (H) ) and higher stability constants of Ln(III) complexes were found for AE-DO3A with respect to DMAE-DO3A (i.e., log KGd-AE-DO3A =22.40 and log KGd-DMAE-DO3A =20.56). The transmetallation reactions of Gd(III) complexes are very slow (Gd-AE-DO3A: t1/2 =2.7×10(4) â h; Gd-DMAE-DO3A: 1.1×10(5) â h at pHâ 7.4 and 298â K) and occur through proton-assisted dissociation.
Assuntos
Meios de Contraste/química , Gadolínio/química , Compostos Heterocíclicos com 1 Anel/química , Elementos da Série dos Lantanídeos/química , Concentração de Íons de Hidrogênio , Cinética , Espectroscopia de Ressonância Magnética , Prótons , Termodinâmica , ÁguaRESUMO
The heptadentate ligand OBETA (2,2'-oxybis(ethylamine)-N,N,N',N'-tetraacetic acid) was reported to form complexes with Ln(3+) ions more stable than those formed by the octadentate and more popular congener EGTA (ethylene glycol O,O'-bis(ethylamine)-N,N,N',N'-tetraacetic acid). The structural features leading to this puzzling coordination paradox were investigated by X-ray diffraction, solution state NMR, molecular modeling, and relaxometric studies. The stability constant of Gd(OBETA) (log KGdL = 19.37, 0.1 M KCl) is 2 orders of magnitude higher than that of the higher denticity analogue Gd(EGTA) (log KGdL = 17.66, 0.1 M KCl). The half-lives (t1/2) for the dissociation reactions of Gd(OBETA) and Gd(EGTA) ([Cu(2+)]tot = 0.2 mM, [Cit(3-)]tot = 0.5 mM, [PO4(3-)]tot = 1.0 mM, and [CO3(2-)]tot = 25 mM at pH = 7.4 and 25 °C in 0.1 M KCl solution) are 6.8 and 0.63 h, respectively, reflecting the much higher inertness of Gd(OBETA) near physiological conditions. NMR studies and DFT calculations using the B3LYP functional and a large-core ECP indicate that the [Gd(OBETA)(H2O)2](-) complex most likely exists in solution as the Δ(λλ)(δδδδ)A/Λ(δδ)(λλλλ)A enantiomeric pair, with an activation free energy for the enantiomerization process of â¼40 kJ·mol(-1). The metal ion is nine-coordinate by seven donor atoms of the ligand and two inner-sphere water molecules. The X-ray crystal structure of [C(NH2)3]3[Lu(OBETA)(CO3)]·2H2O is in agreement with the predictions of DFT calculations, the two coordinated water molecules being replaced by a bidentate carbonate anion. The (1)H NMRD and (17)O NMR study revealed that the two inner-sphere water molecules in Gd(OBETA) are endowed with a relatively fast water exchange rate (kex(298) = 13 × 10(6) s(-1)). The higher thermodynamic stability and inertness of Ln(OBETA) complexes, peaking in the center of the 4f series, combined with the presence of two coordinated water molecules suggests that Gd(OBETA) is a promising paramagnetic probe for MRI applications.
Assuntos
Compostos Organometálicos/química , Cristalografia por Raios X , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura MolecularRESUMO
Cytotoxicity in the µM range was observed in cancer cell lines treated with N,N,N',N'-tetrabenzyl-4,5-diamino-2-cyclopentenone. Cell cycle analysis on HeLa cells showed a clear G1 phase arrest. A preliminary SAR on structural analogs was performed in order to identify the pharmacophores.
Assuntos
Antineoplásicos/farmacologia , Diaminas/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diaminas/síntese química , Diaminas/toxicidade , Relação Dose-Resposta a Droga , HumanosRESUMO
OBETA, OBETA, you bet: Thermodynamic and kinetic measurements show an apparent paradox. The stability of complexes of lanthanide trivalent ions is higher with the heptadentate ligand OBETA (ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid) than with its octadentate homologue EGTA (2,2'-oxybis(ethylamine)-N,N,N',N'-tetraacetic acid). The unusual properties of Gd(OBETA)(-) (see structure), combined with the presence of two fast exchanging coordinated water molecules, candidates this complex as an MRI contrast agent.
Assuntos
Quelantes/química , Ácido Egtázico/análogos & derivados , Ácido Egtázico/química , Gadolínio/química , Elementos da Série dos Lantanídeos/química , Meios de Contraste/química , Ligantes , Imageamento por Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Estereoisomerismo , Termodinâmica , Água/químicaRESUMO
Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1 co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABA(A) receptor (GABA(A)R) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1 could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1 significantly increased the amplitude of miniature inhibitory postsynaptic currents, accelerated their onset, and prolonged the decay kinetics. This compound enhanced also the amplitude of currents elicited by 3 µM GABA and accelerated their fading, reducing, however, currents evoked by a saturating (10 mM) GABA concentration. Moreover, kinetic analysis of responses to 10 mM GABA revealed that 1 upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1 exerts a potent modulatory action on GABA(A)Rs, possibly by modulating agonist binding and desensitization, overall potentially decreasing the toxicity of co-occurring GABA-inhibiting convulsant toxins.
Assuntos
Di-Inos/farmacologia , Álcoois Graxos/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Ácido gama-Aminobutírico/análise , Animais , Di-Inos/química , Enedi-Inos/química , Enedi-Inos/farmacologia , Álcoois Graxos/química , Hipocampo/metabolismo , Cinética , Neurônios/metabolismo , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Exemestane, a 3rd-generation aromatase inhibitor, is clinically used in the treatment of breast cancer in postmenopausal women. The key step of the industrial synthetic process, i.e., a dehydrogenation to introduce the Δ1-unsaturation, is normally performed with quinones such as p-chloranil or DDQ. We observed the formation of two different hexacyclic by-products, depending on the quinone used in the oxidation step. These compounds arise from an initial [4+2] cycloaddition between the precursor 6-methylenandrost-4-ene-3,17-dione and the quinone reagent, followed by a twofold dehydrohalogenation (with p-chloranil) or dehydrogenation (with DDQ). The structures of these unprecedented hexacyclic adducts were determined by a combination of mass spectrometry, NMR techniques and crystallographic analysis.
Assuntos
Androstadienos/química , Benzoquinonas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Difração de Raios XRESUMO
Prompted by the favourable relaxometric, thermodynamic and kinetic properties of the bis-hydrated Gd(OBETA) (OBETA=2,2'-oxybis(ethylamine)-N,N,N',N'-tetraacetic acid) complex, a novel derivative tailored with an n-hexadecyl chain was synthesised. The amphiphilic gadolinium complex was designed and prepared with the aim of obtaining high relaxivity supramolecular aggregates by self-assembly in micelles and liposomes. Thus, lipidic nanoparticles were prepared and characterised by dynamic light scattering and 1 Hâ NMR relaxometry. Relaxivity values of up to 48.3â mm-1 s-1 (20â MHz and 298â K) were registered in liposomal aggregates. The binding to human serum albumin (HSA), evaluated both in terms of affinity and relaxometric properties of the supramolecular adduct, yielded exceptionally high relaxivity values (71.4â mm-1 s-1 at 30â MHz and 298â K).
RESUMO
Polyacetylenes are a class of polyketides related to fatty acids that occur in plants, fungi, marine organisms and animals. These compounds show a pleiotropic profile of bioactivity, that includes antitumor, antibacterial, antimicrobial or antifungal properties. Because of this, the literature on these compounds has grown exponentially, and this review aims at summarizing the inventory of polyacetylenes occurring in terrestrial eukaryotic organisms (plants and fungi) during the last 15 years, and at discussing progress in their bioactivities and in the identification of their biological targets.
Assuntos
Fungos/química , Plantas Medicinais/química , Policetídeos/química , Poli-Inos/química , Animais , Humanos , Estrutura MolecularRESUMO
Difluprednate, a FDA approved topical corticosteroid indicated for the treatment of inflammation and pain associated with ocular surgery, affords three polymorphic crystal forms (one hexagonal, sg. P65, and two distinct orthorhombic, both sg.'s P212121, phases), whose preparation, thermal stability ranges, crystal structures and stereochemical preferences are here reported. Using DSC, single-crystal structural analysis and less conventional ab-initio X-ray powder diffraction methods, the rich structural and thermal behavior of three difluprednate polymorphs have been clarified, and the validity of previous complex and sometimes contradicting literature reports has been challenged. Complementary solution state NMR provided (1)H, (13)C and (19)F chemical shifts full assignment of the corresponding signals. These results allow us to precisely describe the selective isolation pathways toward three distinct crystal phases, and to define their structural and analytical data necessary for identification and easy and accurate quantification, by modern Rietveld analysis, of complex difluprednate polymorphic mixtures, often obtained as a result of poorly controlled (co)-precipitation methods.
Assuntos
Fluprednisolona/análogos & derivados , Varredura Diferencial de Calorimetria , Cristalização , Fluprednisolona/química , Espectroscopia de Ressonância Magnética , Difração de Raios XRESUMO
Two rare cadinane-type sesquiterpenes, lyophyllone A (1) and lyophyllanetriol A (2), were isolated from the mushroom Lyophyllum transforme. The structures were elucidated on the basis of exhaustive NMR techniques, together with MS, UV-Vis and molecular modelling. The absolute configuration of lyophyllone A was determined by ab initio theoretical CD calculation performed by Density Functional Theory (DFT) using the B3PW91/6-31G(d,p) basis set. The experimental CD were found to be in good agreement with the corresponding population-weighted theoretical CD spectra, allowing for the determination of the absolute stereochemistry of the compound.
Assuntos
Agaricales/química , Sesquiterpenos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Conformação Molecular , Teoria Quântica , Sesquiterpenos/químicaRESUMO
Oenanthotoxin (OETX) and dihydro-OETX are polyacetylenic diols occurring in Oenanthe crocata and are known to exert proconvulsant effects. We have recently demonstrated that these compounds downregulated GABAergic currents (Appendino et al., 2009) and that OETX induced open channel block and allosterically modulated GABA(A) receptors (Wyrembek et al., 2010). O. crocata also contains several minor OETX analogues and in the present study we tested whether their effect on GABA(A) receptors depends on the compounds' polarity. We investigated a series of five polyacetylenes characterized by a higher lipophylicity than OETX, (1-acetyl-2,3-dihydrooenanthotoxin - X1, 14-acetyloenanthotoxin-X2, 1-deoxyoenanthotoxin - X3, 14-deoxyoenanthotoxin - X4, 14-dehydro-1-deoxyOETX - X5, polarity sequence: X1>X2>X3>X4>X5). Their effects were tested first on miniature inhibitory postsynaptic currents (mIPSCs). All but X3, significantly decreased the mIPSC amplitudes while X1, X2, X4 decreased, and X3 and X5 increased the mIPSC frequency. The lack of a clear correlation between the compounds' polarity and their effect on mIPSCs might result from their presynaptic effects. We thus considered their impact on current responses to exogenous GABA applications. Amplitude reduction of current responses was most prominent for X1 and virtually absent for X5 indicating a dependence on the compound's polarity. Only X1 and X2 showed open channel block, while the kinetics of currents were affected only by X1 which further supports a dependence of the drug's effects on their polarity. In conclusion, GABA(A) receptors are inhibited and allosterically modulated by naturally occurring OETX analogues (except X5) and these effects are positively correlated with the compounds' polarity.
Assuntos
Enedi-Inos/química , Álcoois Graxos/química , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Poli-Inos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Anticonvulsivantes/química , Anticonvulsivantes/isolamento & purificação , Anticonvulsivantes/farmacologia , Células Cultivadas , Convulsivantes/química , Convulsivantes/isolamento & purificação , Convulsivantes/farmacologia , Descoberta de Drogas , Enedi-Inos/farmacologia , Álcoois Graxos/farmacologia , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/isolamento & purificação , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/isolamento & purificação , Hipocampo/citologia , Hipocampo/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Estrutura Molecular , Neurônios/citologia , Neurônios/metabolismo , Oenanthe/química , Raízes de Plantas/química , Poli-Inos/química , Poli-Inos/isolamento & purificação , Ratos , Ratos WistarRESUMO
Phytocannabinoids like ∆(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) show a beneficial effect on neuroinflammatory and neurodegenerative processes through cell membrane cannabinoid receptor (CBr)-dependent and -independent mechanisms. Natural and synthetic cannabinoids also target the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ), an attractive molecular target for the treatment of neuroinflammation. As part of a study on the SAR of phytocannabinoids, we have investigated the effect of the oxidation modification in the resorcinol moiety of cannabigerol (CBG) on CB(1), CB(2) and PPARγ binding affinities, identifying cannabigerol quinone (VCE-003) as a potent anti-inflammatory agent. VCE-003 protected neuronal cells from excitotoxicity, activated PPARγ transcriptional activity and inhibited the release of pro-inflammatory mediators in LPS-stimulated microglial cells. Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS) was used to investigate the anti-inflammatory activity of this compound in vivo. Motor function performance was evaluated and the neuroinflammatory response and gene expression pattern in brain and spinal cord were studied by immunostaining and qRT-PCR. We found that VCE-003 ameliorated the symptoms associated to TMEV infection, decreased microglia reactivity and modulated the expression of genes involved in MS pathophysiology. These data lead us to consider VCE-003 to have high potential for drug development against MS and perhaps other neuroinflammatory diseases.
Assuntos
Canabinoides/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Quinonas/uso terapêutico , Animais , Infecções por Cardiovirus/tratamento farmacológico , Infecções por Cardiovirus/patologia , Células Cultivadas , Doença Crônica , Citocinas/metabolismo , Dinoprostona/metabolismo , Feminino , Células HEK293 , Humanos , Imuno-Histoquímica , L-Lactato Desidrogenase/metabolismo , Camundongos , Esclerose Múltipla/patologia , Oxirredução , PPAR gama/metabolismo , Gravidez , Desempenho Psicomotor/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Theilovirus , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
A selection of seven phytocannabinoids representative of the major structural types of classic cannabinoids and their corresponding cannabivarins was investigated for in vivo topical anti-inflammatory activity in the Croton oil mouse ear dermatitis assay. Differences in the terpenoid moiety were far more important for anti-inflammatory activity than those at the C-3 alkyl residue, suggesting the involvement not only of cannabinoid receptors, but also of other inflammatory end-points targeted by phytocannabinoids.