RESUMO
Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated inâ vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation.
Assuntos
Butilaminas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Éteres Fenílicos/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Butilaminas/síntese química , Butilaminas/metabolismo , Butilaminas/toxicidade , Células HEK293 , Células HeLa , Humanos , Mexiletina/farmacologia , Simulação de Acoplamento Molecular , Éteres Fenílicos/síntese química , Éteres Fenílicos/metabolismo , Éteres Fenílicos/toxicidade , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/toxicidadeRESUMO
Naturally occurring polyamines like Putrescine, Spermidine, and Spermine are polycations which bind to the DNA, hence stabilizing it and promoting the essential cellular processes. Many synthetic polyamine analogues have been synthesized in the past few years, which have shown cytotoxic effects on different tumours. In the present study, we evaluated the antiproliferative effect of a novel, acylspermidine derivative, (N-(4-aminobutyl)-N-(3-aminopropyl)-8-hydroxy-dodecanamide) (AAHD) on HepG2 cells. Fluorescence staining was performed with nuclear stain (Hoechst 33342) and acridine orange/ethidium bromide double staining. Dose and the time-dependent antiproliferative effect were observed by WST-1 assays, and radical scavenging activity was measured by ROS. Morphological changes such as cell shrinkage & blebbing were analyzed by fluorescent microscopy. It was found that AAHD markedly suppressed the growth of HepG2 cells in a dose- and time-dependent manner. It was also noted that the modulation of ROS levels confirmed the radical scavenging activity. In the near future, AAHD can be a promising drug candidate in chalking out a neoplastic strategy to control the proliferation of tumour cells. This study indicated that AAHD induced anti-proliferative and pro-apoptotic activities on HCC. Since AAHD was active at micromolar concentrations without any adverse effects on the healthy cells (Fibroblasts), it is worthy of further clinical investigations.
Assuntos
Antineoplásicos/farmacologia , Butilaminas/farmacologia , Espermidina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Butilaminas/síntese química , Butilaminas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Estrutura Molecular , Espermidina/síntese química , Espermidina/química , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacosRESUMO
Fourteen ionic liquids (ILs) were obtained and characterized by nuclear magnetic resonance and infra-red spectroscopy. One of these liquids, n-butylammonium acetate, was used in the treatment of coir fiber prior to acid hydrolysis. For this purpose, the fiber was pulped with 8% (w/w) sodium hydroxide for 6h under 2.5 atm pressure at 137°C and then treated with IL for 2h at 90°C. The samples were hydrolyzed in acetic acid at different concentrations and temperatures. The reducing sugar concentrations were determined in all samples, and the optimal hydrolysis conditions were established (32.2% acetic acid at 122.4°C). The reaction time was also studied, and the conversion was maximized at 3h. Under the best hydrolysis conditions, crude fiber, pulping fiber, and IL-treated fiber were hydrolyzed to yield 8.53%, 47.58%, and 89.75% of reducing sugars, respectively.
Assuntos
Butilaminas/química , Celulose/química , Líquidos Iônicos/química , Lignina/química , Ácidos Acíclicos/síntese química , Ácidos Acíclicos/química , Butilaminas/síntese química , Ácidos Graxos/síntese química , Ácidos Graxos/química , Hidrólise , Líquidos Iônicos/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Potent and selective adenosine A1 receptor (A1AR) antagonists with favourable pharmacokinetic properties used as novel diuretics and antihypertensives are desirable. Thus, we designed and synthesized a series of novel 4-alkylamino substitution-2-arylpyrazolo[4,3-c]quinolin-3-one derivatives. The aim of the present study is to characterize the biological profiles of the optimized compound, PQ-69. In vitro binding assay revealed a K i value of 0.96 nM for PQ-69 in cloned hA1 receptor, which was 217-fold more selective compared with hA2A receptors and >1,000-fold selectivity for hA1 over hA3 receptor. The results obtained from [(35)S]-GTPγS binding and cAMP concentration assays indicated that PQ-69 might be an A1AR antagonist with inverse agonist activity. In addition, PQ-69 displayed highly inhibitory activities on isolated guinea pig contraction (pA2 value of 8.99) induced by an A1AR agonist, 2-chloro-N6-cyclopentyl adenosine. Systemic administration of PQ-69 (0.03, 0.3, 3 mg/kg) increased urine flow and sodium excretion in normal rats. Furthermore, PQ-69 displayed better metabolic stability in vitro and longer terminal elimination half-life (t 1/2) in vivo compared with 1,3-dipropyl-8-cyclopentylxanthine. These findings suggest that PQ-69 exhibits potent antagonist effects on A1AR in vitro, ex vivo and in vivo, it might be a useful research tool for investigating A1AR function, and it could be developed as a potential therapeutic agent.
Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Butilaminas/farmacocinética , Quinolonas/farmacocinética , Animais , Butilaminas/síntese química , Células CHO , Cricetulus , Cobaias , Células HEK293 , Humanos , Masculino , Quinolonas/síntese química , Ratos , Ratos Sprague-DawleyRESUMO
Ionic clathrate hydrates are water-based materials that have unique properties, such as a wide range of melting temperatures and high gas capacities. In their structure, water molecules coordinate around ionic substances, which is regarded as the actual hydration structure and also linking of the hydrate clusters, giving insight into the dynamics of the water molecules and ions. This paper reports the synthesis and characterization of the ionic clathrate hydrate of tetra-n-butylammonium lactate (TBAL), the anion of which is a biological organic material. Phase equilibrium measurements and optical observations of the crystal morphology and crystal structure analysis were performed. The TBAL hydrate has a melting temperature of 284.8 K suitable for cool energy storage applications. The actual hydration patterns around a lactate anion are shown in the form of ionic clathrate hydrate structure.
Assuntos
Butilaminas/química , Butilaminas/síntese química , Ácido Láctico/química , Ácido Láctico/síntese química , Água/química , Íons/química , Estrutura MolecularRESUMO
Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [(35)S]GTPγS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50 = 59 nM, α = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, α = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R.
Assuntos
Butilaminas/síntese química , Butilaminas/farmacologia , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/síntese química , Histamina/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Histamínicos H3/efeitos dos fármacos , Receptores Histamínicos/efeitos dos fármacos , Animais , Desenho de Fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Histamina/análogos & derivados , Histamina/metabolismo , Agonistas dos Receptores Histamínicos/metabolismo , Humanos , Ligantes , Estrutura Molecular , Ensaio Radioligante , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/genética , Receptores Histamínicos/metabolismo , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H4 , Células Sf9 , Spodoptera , Relação Estrutura-Atividade , TransfecçãoRESUMO
A series of indolebutylamine derivatives were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine 3 receptor. The most potent compound 11q binds to dopamine 3 receptor with a Ki value of 124 nm and displays excellent selectivity over the dopamine 1 receptor and dopamine 2 receptor. Investigation based on structural information indicates that site S182 located in extracellular loop 2 may account for high selectivity of compounds. Interaction models of the dopamine 3 receptor-11q complex and structure-activity relationships were discussed by integrating all available experimental and computational data with the eventual aim to discover potent and selective ligands to dopamine 3 receptor.
Assuntos
Acetanilidas/síntese química , Butilaminas/química , Antagonistas de Dopamina/síntese química , Desenho de Fármacos , Indóis/química , Indóis/síntese química , Receptores de Dopamina D3/antagonistas & inibidores , Acetanilidas/química , Acetanilidas/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Butilaminas/síntese química , Butilaminas/metabolismo , Domínio Catalítico , Antagonistas de Dopamina/química , Antagonistas de Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2 , Células HEK293 , Humanos , Indóis/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Ligação Proteica , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Relação Estrutura-AtividadeRESUMO
The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit K(i)(app) ≤ 10 nM and GI(50) ≈ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.
Assuntos
Antineoplásicos/síntese química , Derivados de Benzeno/síntese química , Butilaminas/síntese química , Cinesinas/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Derivados de Benzeno/farmacocinética , Derivados de Benzeno/farmacologia , Disponibilidade Biológica , Butilaminas/farmacocinética , Butilaminas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Ligação Proteica , Conformação Proteica , Quinazolinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
The ring expansion of cyclopropane derivatives provides a powerful method to construct synthetically useful four-membered carbocycles. Herein, a new type of gold(I)-catalyzed ring expansion of an unactivated alkynylcyclopropane/sulfonamide trapping strategy to (E)-2-alkylidenecyclobutanamines was described. The reaction tolerates a range of aryl and alkyl substituents with moderate to good yields.
Assuntos
Alcinos/química , Butilaminas/síntese química , Ciclobutanos/síntese química , Ciclopropanos/química , Ouro/química , Sulfonamidas/química , Butilaminas/química , Catálise , Técnicas de Química Combinatória , Ciclização , Ciclobutanos/química , Estrutura Molecular , EstereoisomerismoRESUMO
Ten beta-trifluoroalkyl aminovinyl ketone derivatives were synthesized, and their inhibitory effects on several phytopathogenic fungi, an oomycete and plants were assessed. The various compounds were fungitoxic at the 10-100 microM range, with (Z)-3-amino-4,4,4-trifluoro-1-(4-chlorophenyl)but-2-en-1-one exhibiting the highest inhibitory effect on most of the test pathogens. Alternaria alternata and Neurospora crassa were the most tolerant and sensitive fungi to the compounds, respectively. We propose that (Z)-3-amino-4,4,4-trifluoro-1-phenylbut-2-en-1-one is the minimal structural requirement for a beta-trifluoroalkyl aminovinyl ketone fungitoxic derivative.
Assuntos
Butanonas/síntese química , Butanonas/farmacologia , Butilaminas/síntese química , Butilaminas/farmacologia , Fungos/efeitos dos fármacos , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Alternaria/efeitos dos fármacos , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Neurospora crassa/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The first proof-of-concept of the formation of a double tert-butylamine (t-BuNH(2)) + hydrogen (H(2)) clathrate hydrate has been demonstrated. Binary clathrate hydrates with different molar concentrations of the large guest t-BuNH(2) (0.98-9.31 mol %) were synthesized at 13.8 MPa and 250 K, and characterized by powder X-ray diffraction and Raman microscopy. A structural transformation from sVI to sII of t-BuNH(2) hydrate was clearly observed under hydrogen pressures. Raman spectroscopic data suggested that the hydrogen molecules occupied the small cages and had similar occupancy to hydrogen in the double tetrahydrofuran (THF) + H(2) clathrate hydrate. The hydrogen storage capacity in this system was approximately 0.7 H(2) wt % at the molar concentration of t-BuNH(2) close to the sII stoichiometry.
Assuntos
Butilaminas/química , Hidrogênio/química , Butilaminas/síntese química , Difração de Pó , Análise Espectral Raman , Água/químicaRESUMO
In this study, 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, (BR-AEA), was designed, synthesized, characterized and tested in docking studies and in vitro. Previous to its synthesis, a set of compounds, including well-known ligands and boron containing compounds, were studied under docking simulations. BR-AEA showed greater affinity than these well-known agonists and was found to be slightly closer than salbutamol to the residues in the TM5 and TM3 of the beta(2) adrenoceptor (beta(2)AR), making a greater number of interactions with them, including some that are apparently key to greater affinity and beta(2)AR activation. This study suggests that affinity is closely related to the interactions of the boron atom, as well as the capacity of boronic acid moieties to make a network of hydrogen bonds with the beta(2)AR. In vitro, the relaxing effects of BR-AEA on isolated guinea pig tracheal rings were compared with salbutamol. The EC(50) values for BR-AEA were at least five-fold lower than for salbutamol, showing the greater potency of the former. Additionally, propranolol and ICI 118,551 showed competitive antagonism in relation to the relaxing effect of the test compound (pA(2) 6.204+/-0.367 and 9.089+/-0.470, respectively).
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Butilaminas/síntese química , Butilaminas/farmacologia , Biologia Computacional , Desenho de Fármacos , Etanol/síntese química , Etanol/farmacologia , Albuterol/análogos & derivados , Animais , Sítios de Ligação , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/metabolismo , Butilaminas/química , Butilaminas/metabolismo , Etanol/química , Etanol/metabolismo , Cobaias , Humanos , Ligantes , Masculino , Modelos Moleculares , Conformação Molecular , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismoRESUMO
A very efficient synthesis of (2R,3S) and (2S,3R)-4-aminobutane-1,2,3-triol has been developed using either d- or l-glucose as the starting material. A key step is the one-pot conversion of an aldehyde to an amide, the scope of which has been extended to include other carbohydrate-derived aldehydes.
Assuntos
Álcoois/síntese química , Butilaminas/síntese química , Álcoois/química , Butilaminas/química , Glucose/química , Estrutura Molecular , EstereoisomerismoRESUMO
Optically active trans-tert-butyl-2-aminocyclopentylcarbamate (1) has potential utility as a scaffold for chiral ligands and as a modified backbone unit for peptide nucleic acids (PNAs). We have developed a short and practical synthesis of 1 via aziridine opening of tosyl-activated cyclopentene aziridine 2 and optical resolution of racemic 1 with 10-camphorsulfonic acid (CSA). The route provides ready access to multigram quantities of both enantiomers without the need for chromatography.
Assuntos
Aziridinas/química , Butilaminas/síntese química , Carbamatos/síntese química , Ciclopentanos/química , Azidas/química , Butilaminas/química , Carbamatos/química , Estrutura Molecular , EstereoisomerismoRESUMO
The syntheses of three diacetylenic isobutylamides of Echinacea angustifolia have been achieved by direct synthetic routes by way of a common intermediate. The key step is the alkylation of the anion of the silylated diacetylene. We report the presence of all three diacetylenic isobutylamides in six of the nine Echinacea species: E. angustifolia, E. sanguinea, E. simulata, E. tennesseensis, E. atrorubens and E. laevigata. The accumulation of these amides is sensitive to organ type and age.
Assuntos
Acetileno/análogos & derivados , Butilaminas/metabolismo , Echinacea/metabolismo , Acetileno/síntese química , Acetileno/metabolismo , Butilaminas/síntese química , Cromatografia Líquida de Alta Pressão , Flores/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Estrutura Molecular , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo , Especificidade da Espécie , Distribuição TecidualRESUMO
Two new (11)C-labelled ligands, N-(3-(4-hydroxyphenyl)propyl)-3-(4-methoxyphenyl)propylamine ([(11)C]2) and N-(3-(4-hydroxyphenyl)butyl)-3-(4-methoxyphenyl)butylamine ([(11)C]3) were designed based on bis(phenylalkyl)amines (1) which have been reported as polyamine site antagonists with high-selectivity for NR1A/2B NMDA receptors, and radiolabelling of the corresponding phenol precursors with [(11)C]methyl iodide was readily accomplished. The in vitro inhibition experiments using rat brain slices showed that [(11)C]2 and [(11)C]3 share the binding sites with spermine and/or ifenprodil but not with CP-101,606, a highly potent NR2B-selective NMDA antagonist, and that divalent cations such as Zn(2+) produced significant inhibition of both [(11)C]2 and [(11)C]3 bindings. Intravenous injection of [(11)C]3 in mice showed almost homogeneous distribution throughout the brain. Attempts to block the tracer uptake of [(11)C]3 by pre-injection with the unlabelled 3 or spermine in rats were unsuccessful, but a small decrease in the cerebral uptake of [(11)C]3 by co-treatment with the unlabelled 3 was observed in a monkey PET study. The present findings indicate that none of these (11)C-labelled analogues have potential for PET study of binding sites on the N-methyl-D-aspartate (NMDA) receptors.
Assuntos
Aminas/farmacologia , Encéfalo/efeitos dos fármacos , Butilaminas/farmacologia , Propilaminas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Encéfalo/metabolismo , Butilaminas/síntese química , Butilaminas/farmacocinética , Radioisótopos de Carbono , Técnicas In Vitro , Injeções Intravenosas , Marcação por Isótopo , Macaca mulatta , Masculino , Camundongos , Piperidinas/farmacologia , Propilaminas/síntese química , Propilaminas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Espermina/farmacologia , Distribuição TecidualRESUMO
New nitro- and aminoquinoline derivatives containing a pyridyl nucleus were synthesized from 6, 8-disubstituted 4-methyl-2-pyridylquinolines, which were prepared from N-pyridylmethylidenanilines. The anti-chagasic and trichomonacidal in vitro activity, as well as the cytotoxic properties towards macrophages of some of these compounds were evaluated. Although some of the compounds showed only moderate activity it was possible to establish some structure-activity relationships.
Assuntos
Aminoquinolinas/síntese química , Compostos de Anilina/síntese química , Antitricômonas/síntese química , Butilaminas/síntese química , Compostos Heterocíclicos/síntese química , Nitroquinolinas/síntese química , Tripanossomicidas/síntese química , Aminoquinolinas/farmacologia , Compostos de Anilina/farmacologia , Animais , Antitricômonas/farmacologia , Butilaminas/farmacologia , Linhagem Celular , Compostos Heterocíclicos/farmacologia , Técnicas In Vitro , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Metronidazol/farmacologia , Nifurtimox/farmacologia , Nitroquinolinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacosAssuntos
Antineoplásicos/química , Butilaminas/química , Cisplatino/química , Compostos Organoplatínicos/química , Butilaminas/síntese química , Cisplatino/síntese química , Desenho de Fármacos , Hidrólise , Espectroscopia de Ressonância Magnética , Compostos Organoplatínicos/síntese química , Oxirredução , Espectrometria de Massas por Ionização por Electrospray , EstereoisomerismoRESUMO
We designed a new type of spin-labeled nucleosides with an N-tert-butylaminoxyl radical which is introduced to the nucleobase directly. Purine and pyrimidine ribonucleosides containing the aminoxyl radical such as 1a-d, 2, 3, and 4 were synthesized to investigate the stability and behavior of the N-tert-butylaminoxyl radical on a nucleobase. Lithiation of tri-O-silylated 6-chloropurine ribonucleoside (5) followed by reaction with 2-methyl-2-nitrosopropane (MNP) gave the key compound 6a, which was further converted to 6b-d. Oxidation of the obtained 6a-d and their triols (7a-d) with Ag(2)O led to formation of the corresponding stable spin-labeled nucleosides (8a-d and 1a-d), which were confirmed by EPR spectroscopy. Similarly, the precursors of spin-labeled pyrimidines (13, 20, and 23) were synthesized by site-selective lithiation of tri-O-protected pyrimidine derivatives (9, 18, and 21) followed by the reaction with MNP and deprotection. An EPR study showed that the aminoxyl radicals (2, 3, and 4) were stable and that their hyperfine structures were dependent on the position of the radical. Electron densities of pyrimidine also affected hyperfine structures.
Assuntos
Butilaminas/síntese química , Ribonucleosídeos/síntese química , Marcadores de Spin/síntese química , Desenho de Fármacos , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres/química , Purinas/química , Pirimidinas/química , Ribonucleosídeos/químicaRESUMO
(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).