RESUMEN
In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.
Asunto(s)
Supervivencia Celular , Ciclohexilaminas , Diseño de Fármacos , Ferroptosis , Células Endoteliales de la Vena Umbilical Humana , Piperazinas , Humanos , Ferroptosis/efectos de los fármacos , Piperazinas/farmacología , Piperazinas/síntesis química , Piperazinas/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Relación Estructura-Actividad , Ciclohexilaminas/farmacología , Ciclohexilaminas/química , Ciclohexilaminas/síntesis química , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Fenilendiaminas/farmacología , Fenilendiaminas/química , Fenilendiaminas/síntesis química , Relación Dosis-Respuesta a Droga , Especies Reactivas de Oxígeno/metabolismo , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/química , Compuestos Ferrosos/síntesis química , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
An abundant sponge of the order Bubarida was selected for further chemical investigation following biological and chemical screening of sponges collected from Futuna Islands in the Indo-Pacific. Ten new nitrogenous bisabolene derivatives were isolated and identified: the monomeric theonellin formamide analogues named bubaridins A-F (1-6) with unusual oxidised linear chains, and the first isocyanide/formamide dimeric and cyclised bisabolenes 7-9. The structure elucidation of these nitrogenous bisabolenes involved HRESIMS, NMR, and ECD analyses, and the chiral compounds were found to be racemates. A biosynthetic hypothesis for the production of these metabolites is proposed and some chemotaxonomic considerations are discussed. Furthermore, the antimicrobial and antitumoral activity were evalutated and the trans-dimer theonellin isocyanide (7) was shown to exhibit potent and selective antifungal activity.
Asunto(s)
Antifúngicos/farmacología , Ciclohexilaminas/farmacología , Sesquiterpenos Monocíclicos/farmacología , Poríferos/química , Animales , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Candida/efectos de los fármacos , Línea Celular Tumoral , Ciclohexilaminas/síntesis química , Ciclohexilaminas/aislamiento & purificación , Humanos , Islas , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Sesquiterpenos Monocíclicos/química , Sesquiterpenos Monocíclicos/aislamiento & purificación , Océano PacíficoRESUMEN
Photodynamic therapy (PDT) is a non-invasive treatment method for tumors by exciting photosensitizers (PS) upon light irradiation to generate cytotoxic reactive oxygen species (ROS). However, the low oxygen concentration near the tumor tissue limits the therapeutic effect of PDT. Herein, we synthesized six chlorin e6 derivatives containing NO-donors to enhance their antitumor activity by synergistic effect of ROS and NO. The results revealed that the new NO-donor containing photosensitizers (PS-NO) exhibited more potent photodynamic activity than chlorin e6, and the introduction of NO donor moieties to chlorin e6 increased the level of NO and ROS in cells. The addition of Ferrostatin-1, a ferroptosis inhibitor, markedly reduced the photodynamic activity of PS-NO as well as the level of NO and ROS in cells. Mechanism studies further showed that PS-NO could reduce intracellular GSH level, inhibit GPX4 activity and promote malondialdehyde (MDA) accumulation upon light irradiation, which suggested the ferroptosis mechanism underlying the PDT effect of PS-NO.
Asunto(s)
Ciclohexilaminas/farmacología , Fenilendiaminas/farmacología , Fármacos Fotosensibilizantes/farmacología , Ciclohexilaminas/síntesis química , Ciclohexilaminas/química , Relación Dosis-Respuesta a Droga , Ferroptosis/efectos de los fármacos , Células HeLa , Humanos , Estructura Molecular , Óxido Nítrico/análisis , Óxido Nítrico/metabolismo , Fenilendiaminas/síntesis química , Fenilendiaminas/química , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
DNA-cleavage agents such as bleomycin have potential anticancer applications. The development of a DNA-cleavage reagent that recognizes specific sequences allows the development of cancer therapy with reduced side effects. In this study, to develop novel compounds with specific DNA-cleavage activities, we synthesized optically active binuclear ligands, (1R,1'R,2R,2'R)-N1,N1'-(meta/para-phenylenebis(methylene))bis(N2,N2-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine) and their enantiomers. The DNA-cleavage activities of these compounds were investigated in the presence of Fe(II)SO4 and sodium ascorbate. The obtained results indicated that the Fe(II) complexes of those compounds efficiently cleave DNA and that their cleavage was subtle sequence-selective. Therefore, we succeeded in developing compounds that can be used as small-molecule drugs for cancer chemotherapy.
Asunto(s)
Ciclohexilaminas/farmacología , Compuestos Ferrosos/farmacología , Ciclohexilaminas/síntesis química , Ciclohexilaminas/química , División del ADN , Relación Dosis-Respuesta a Droga , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Ligandos , Estructura Molecular , Plásmidos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate-dependent enzyme, plays a critical role in the progression of hepatocellular carcinoma (HCC). Pharmacological selective inhibition of hOAT has been shown to be a potential therapeutic approach for HCC. Inspired by the discovery of the nonselective aminotransferase inactivator (1R,3S,4S)-3-amino-4-fluoro cyclopentane-1-carboxylic acid (1), in this work, we rationally designed, synthesized, and evaluated a novel series of fluorine-substituted cyclohexene analogues, thereby identifying 8 and 9 as novel selective hOAT time-dependent inhibitors. Intact protein mass spectrometry and protein crystallography demonstrated 8 and 9 as covalent inhibitors of hOAT, which exhibit two distinct inactivation mechanisms resulting from the difference of a single fluorine atom. Interestingly, they share a similar turnover mechanism, according to the mass spectrometry-based analysis of metabolites and fluoride ion release experiments. Molecular dynamics (MD) simulations and electrostatic potential (ESP) charge calculations were conducted, which elucidated the significant influence of the one-fluorine difference on the corresponding intermediates, leading to two totally different inactivation pathways. The novel addition-aromatization inactivation mechanism for 9 contributes to its significantly enhanced potency, along with excellent selectivity over other aminotransferases.
Asunto(s)
Ácidos Ciclohexanocarboxílicos/química , Ciclohexilaminas/química , Inhibidores Enzimáticos/química , Hidrocarburos Fluorados/química , Ornitina-Oxo-Ácido Transaminasa/antagonistas & inhibidores , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/metabolismo , Ciclohexilaminas/síntesis química , Ciclohexilaminas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/metabolismo , Modelos Químicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Ornitina-Oxo-Ácido Transaminasa/química , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Unión Proteica , Fosfato de Piridoxal/química , Ácido gamma-Aminobutírico/análogos & derivadosRESUMEN
The syntheses of conduramine B-2, ent-conduramine F-2, aminocyclopentitol and trihydroxyazepane were accomplished from a common precursor, through a divergent approach using ring closing metathesis (RCM) as the key step. Tri-O-benzyl-d-glucal was converted to 3,4,6-tri-O-benzyl-1,2-dideoxy-2-iodo-1-p-toluenesulfonamido-α-d-mannose. Exposure to NaBH4 in MeOH resulted in a facile 1,2-transposition of the -NHTs group with concomitant glycosylation to give methyl 3,4,6-tri-O-benzyl-2-deoxy-2-p-toluenesulfonamido-ß-d-glucoside, which was converted into methyl 6-deoxy-6-iodo-glucoside in three steps. Zinc-mediated Vasella's rearrangement proceeded smoothly to give the pluripotent formyl-olefin, possessing both electrophilic and nucleophilic sites, which was used as a common precursor in our diversity-oriented approach. Vinylation of the carbonyl group followed by RCM and subsequent deprotection resulted in the successful synthesis of conduramine B-2 and ent-conduramine F-2 for the first time. On the other hand, the Wittig reaction of the formyl-olefin affords the diene that undergoes Grubbs' I catalyzed RCM and deprotection/reduction to provide 3-amino-cyclopentan-1,2-diol. Utilizing the nucleophilic site at the nitrogen of the common precursor, base mediated N-allylation was carried out to obtain the corresponding diene that underwent a smooth RCM to afford trihydroxyazepane.
Asunto(s)
Azepinas/síntesis química , Ciclohexanoles/síntesis química , Ciclohexilaminas/síntesis química , Ciclopentanos/síntesis química , Azepinas/química , Ciclohexanoles/química , Ciclohexilaminas/química , Ciclopentanos/química , Glicosilación , Estructura MolecularRESUMEN
Inspite of progress made for the discovery of novel antiepileptic drugs, epilepsy remains an unmet medical need. We synthesized nine trifluoromethylated enaminone derivatives and tested them for their anticonvulsant activity using maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and rotorod test for neurotoxicity. Among the compounds tested 3-(4-fluoro-3-(trifluomethyl)benzylamino)-5-(trifluoromethyl)cyclohex-2-enone (4f) showed ED50 of 23.47â¯mg/kg, when given orally to rats, 3-(4-chlorophenylamino)-5-(trifluoromethyl)cyclohex-2-enone (5a), which was previously reported by us but for which no quantitative data was available at the time, exhibited an ED50 of 62.39â¯mg/kg. Under the same conditions commercially available carbamazepine showed an ED50 of 28.20â¯mg/kg. There were no neurotoxicity observed upto a dose of 300â¯mg/kg for all the tested compounds. Compounds 4f and 5a represent good lead compounds for further development.
Asunto(s)
Anticonvulsivantes/farmacología , Bencilaminas/farmacología , Ciclohexanonas/farmacología , Ciclohexilaminas/farmacología , Hidrocarburos Fluorados/farmacología , Convulsiones/prevención & control , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidad , Bencilaminas/síntesis química , Bencilaminas/farmacocinética , Bencilaminas/toxicidad , Simulación por Computador , Ciclohexanonas/síntesis química , Ciclohexanonas/farmacocinética , Ciclohexanonas/toxicidad , Ciclohexilaminas/síntesis química , Ciclohexilaminas/farmacocinética , Ciclohexilaminas/toxicidad , Diseño de Fármacos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/farmacocinética , Hidrocarburos Fluorados/toxicidad , Masculino , Ratones , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Conductive materials are valuable supports and widely applied in electrochemical analysis. In the current article, a mesoporous organosilica sphere (S,S)-CPMO-3 with the chiral group and electroactive units is presented. The organosilicon framework is composed of free ions belonging to the ionic liquid and the chiral group arising from (1S,2S)-1,2-diaminocyclohexane. Next, a bare electrode was modified by the as-synthesized composite material to construct the new electrochemical sensor (S,S)-CPMO-3-GCE. It was observed that (S,S)-CPMO-3-GCE exhibited favourable enantioselective recognition in the response of the peak current (Ip) and the peak potential (Ep) to the different configurations of amino acids. Taking tryptophan as an example, the value of IL/ID is 13.84 and the peak-to-peak potential approaches 48 mV. In addition, cysteine and tyrosine were successfully distinguished by the sensor. In summary, this study not only introduces a route for the synthesis of a conductive material, but also opens up its further potential in enantioselective recognition.
Asunto(s)
Aminoácidos/análisis , Técnicas Electroquímicas/métodos , Dióxido de Silicio/química , Aminoácidos/química , Ciclohexilaminas/síntesis química , Ciclohexilaminas/química , Cisteína/química , Líquidos Iónicos/síntesis química , Líquidos Iónicos/química , Porosidad , Estereoisomerismo , Triptófano/química , Tirosina/químicaRESUMEN
Ultraviolet-absorbing chemicals are useful in cosmetics and skin care to prevent UV-induced skin damage. We demonstrate here that heterologous production of shinorine, which shows broad absorption maxima in the UV-A and UV-B region. A shinorine producing Corynebacterium glutamicum strain was constructed by expressing four genes from Actinosynnema mirum DSM 43827, which are responsible for the biosynthesis of shinorine from sedoheptulose-7-phosphate in the pentose phosphate pathway. Deletion of transaldolase encoding gene improved shinorine production by 5.2-fold. Among the other genes in pentose phosphate pathway, overexpression of 6-phosphogluconate dehydrogenase encoding gene further increased shinorine production by 60% (19.1 mg/L). The genetic engineering of the pentose phosphate pathway in C. glutamicum improved shinorine production by 8.3-fold in total, and could be applied to produce the other chemicals derived from sedoheptulose-7-phosphate.
Asunto(s)
Corynebacterium glutamicum/metabolismo , Ciclohexilaminas/síntesis química , Glicina/análogos & derivados , Ingeniería Metabólica , Protectores Solares/síntesis química , Actinobacteria/genética , Corynebacterium glutamicum/genética , Genes Bacterianos , Glicina/síntesis química , Espectrometría de Masas , Vía de Pentosa Fosfato , Fosfogluconato Deshidrogenasa/metabolismo , Recombinación Genética , Fosfatos de Azúcar/química , Transaldolasa/genética , Rayos UltravioletaRESUMEN
The glmS ribozyme is a bacterial gene-regulating riboswitch that controls cell wall synthesis, depending on glucosamine-6-phosphate as a cofactor. Due to the presence of this ribozyme in several human pathogen bacteria (e.g., MRSA, VRSA), the glmS ribozyme represents an attractive target for the development of artificial cofactors. The substitution of the ring oxygen in carbohydrates by functionalized methylene groups leads to a new generation of glycomimetics that exploits distinct interaction possibilities with their target structure in biological systems. Herein, we describe the synthesis of mono-fluoro-modified carba variants of α-d-glucosamine and ß-l-idosamine. (5aR)-Fluoro-carba-α-d-glucosamine-6-phosphate is a synthetic mimic of the natural ligand of the glmS ribozyme and is capable of effectively addressing its unique self-cleavage mechanism. However, in contrast to what was expected, the activity is significantly decreased compared to its non-fluorinated analog. By combining self-cleavage assays with the Bacillus subtilis and Staphylococcus aureus glmS ribozyme and molecular docking studies, we provide a structure-activity relationship for fluorinated carba-sugars.
Asunto(s)
Proteínas Bacterianas/metabolismo , Carba-azúcares/metabolismo , ARN Catalítico/metabolismo , Bacillus subtilis/metabolismo , Proteínas Bacterianas/química , Sitios de Unión , Carba-azúcares/síntesis química , Carba-azúcares/química , Ciclohexanoles/síntesis química , Ciclohexanoles/química , Ciclohexanoles/metabolismo , Ciclohexilaminas/síntesis química , Ciclohexilaminas/química , Ciclohexilaminas/metabolismo , Halogenación , Conformación Molecular , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , ARN Catalítico/química , Staphylococcus aureus/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
AIM: Cancer is among the leading causes of death worldwide. Medical interest has focused on macrocyclic polyamines because of their properties as antitumor agents. Results/Methodology: We have designed and synthesized a series of 1,2-diaminocyclohexane derivatives with notable in vitro antiproliferative activities against the MCF-7, HCT-116 and A375 cancer cell lines. Cell cycle and apoptosis analyses were also carried out. Our results show that all the compounds are potent cytotoxic agents, especially against the A375 cell line. CONCLUSION: The selective activity of the macrocyclic derivative against A375, via apoptosis, supposes a great advantage for future therapeutic use. This exemplifies the potential of 1,2-diaminocyclohexane derivatives to qualify as lead structures for future anticancer drug development due to their easy syntheses and noteworthy bioactivity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Ciclohexilaminas/síntesis química , Ciclohexilaminas/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis , Neoplasias de la Mama , Ciclo Celular , Línea Celular Tumoral , Neoplasias del Colon , Ciclohexilaminas/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración 50 Inhibidora , Neoplasias Cutáneas , Relación Estructura-ActividadRESUMEN
IEM-2062 [1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride], causing a combined block NMDA and AMPA receptors, after chronic oral administration in doses, respectively, 0.3 and 3 mg/kg, induce maximal anticonvulsant effect in the pentylenetetrazol kindling rats because decrease the number of completely kindling rats by 100 %, and also decrease in 2.5-3.3 times the average severity of clonic-tonic kindling seizures. IEM-2062 causes significant anticon- 299 vulsant effects in the widest range of doses, 1-48 mg/kg, which is 24-22 times more than that of memantine (12-20 mg/kg) and sodium valproate (100-200 mg/kg). Sodium valproate and memantine cause significant disturbances of locomotor activity in the «open field¼ test in doses causing maximal anticonvulsant effect in the kindling rats. At the same time IEM-2062 cause disturbance of locomotor activity only in very high dose of 92 mg/kg, which exceeds in 30.7 times the dose causing the maximum anticonvulsive effect in the kindling rats. Thus, IEM-2062 reduces the severity of kindling seizures in 1.7-1.9 times stronger than sodium valproate and memantine and also by 30.7 times is safer than sodium valproate and memantine.
Asunto(s)
Anticonvulsivantes/farmacología , Ciclohexanos/farmacología , Ciclohexilaminas/farmacología , Excitación Neurológica/efectos de los fármacos , Memantina/farmacología , Convulsiones/tratamiento farmacológico , Ácido Valproico/farmacología , Administración Oral , Animales , Convulsivantes/administración & dosificación , Ciclohexanos/síntesis química , Ciclohexilaminas/síntesis química , Esquema de Medicación , Excitación Neurológica/metabolismo , Locomoción/efectos de los fármacos , Masculino , Pentilenotetrazol/administración & dosificación , Ratas , Ratas Wistar , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Convulsiones/fisiopatologíaRESUMEN
Aromatic hydrocarbons are some of the most elementary feedstock chemicals, produced annually on a million metric ton scale, and are used in the production of polymers, paints, agrochemicals and pharmaceuticals. Dearomatization reactions convert simple, readily available arenes into more complex molecules with broader potential utility, however, despite substantial progress and achievements in this field, there are relatively few methods for the dearomatization of simple arenes that also selectively introduce functionality. Here we describe a new dearomatization process that involves visible-light activation of small heteroatom-containing organic molecules-arenophiles-that results in their para-cycloaddition with a variety of aromatic compounds. The approach uses N-N-arenophiles to enable dearomative dihydroxylation and diaminodihydroxylation of simple arenes. This strategy provides direct and selective access to highly functionalized cyclohexenes and cyclohexadienes and is orthogonal to existing chemical and biological dearomatization processes. Finally, we demonstrate the synthetic utility of this strategy with the concise synthesis of several biologically active compounds and natural products.
Asunto(s)
Compuestos Azo/química , Derivados del Benceno/química , Ciclohexanoles/síntesis química , Reacción de Cicloadición , Ciclohexilaminas/síntesis química , Hidroxilación , Luz , Estructura Molecular , Fenoles/síntesis químicaRESUMEN
Although NMR in fragment-based drug discovery is utilized almost exclusively to evaluate physical binding between molecules, it should be also a powerful tool for biochemical assay, evaluating inhibitory effect of compounds on enzymatic activity. Time-dependent spectral change in real-time monitoring or inhibitor concentration-dependent spectral change after constant-time reaction was processed by factor analysis, by which reaction rate or IC50 value was obtained. Applications to spermidine synthase of Trypanosoma cruzi, which causes Chagas disease, are described.
Asunto(s)
Ciclohexilaminas/farmacología , Descubrimiento de Drogas , Resonancia Magnética Nuclear Biomolecular , Espermidina Sintasa/antagonistas & inhibidores , Trypanosoma cruzi/enzimología , Enfermedad de Chagas/tratamiento farmacológico , Ciclohexilaminas/síntesis química , Ciclohexilaminas/química , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Estructura Molecular , Espermidina Sintasa/metabolismo , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Three platinum(II) complexes of (1R,2R)-N(1)-cyclopentyl-1,2-cyclohexanediamine with malonate derivatives were designed, synthesized and spectrally characterized. MTT assay showed that the complexes possessed positive cytotoxic effect on the four human solid tumor cell lines. Among the complexes, complex 2 demonstrated the strongest cytotoxic activity compared to cisplatin and oxaliplatin against HepG2 cell line (IC50=3.04µM). Furthermore, the results of gel electrophoresis revealed that complex 2 interacted with DNA in a different mode from that of cisplatin. Mechanism studies of cell proliferation inhibition and cellular uptake indicated that complex 2 entered HepG2 cell more efficiently than cisplatin, exhibited massive G2 accumulation and then induced apoptosis.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Ciclohexilaminas/farmacología , Malonatos/farmacología , Compuestos Organoplatinos/farmacología , Platino (Metal)/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ciclohexilaminas/síntesis química , Ciclohexilaminas/química , División del ADN/efectos de los fármacos , ADN Superhelicoidal/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Malonatos/síntesis química , Malonatos/química , Compuestos Organoplatinos/síntesis química , Relación Estructura-ActividadRESUMEN
The rise in new psychoactive substances that are available as 'research chemicals' (RCs) remains a significant forensic and legislative challenge. A number of arylcyclohexylamines have attracted attention as RCs and continue to be encountered, including 3-MeO-PCP, 3-MeO-PCE and 3-MeO-PCPr. These compounds are commonly perceived as ketamine-like dissociative substances and are believed to act predominantly via antagonism of the N-methyl-D-aspartate (NMDA) receptor. To aid in the identification of newly emerging substances of abuse, the current studies were performed. The syntheses of fifteen N-alkyl-arylcyclohexylamines are described. Analytical characterizations were performed via gas chromatography and high performance liquid chromatography coupled to multiple forms of mass spectrometry as well as nuclear magnetic resonance spectroscopy, ultraviolet diode array detection and infrared spectroscopy. The series consisted of the N-alkyl derivatives (N-methyl, N-ethyl, N-propyl) of phenyl-substituted and isomeric 2-, 3- and 4-methoxy phenylcyclohexylamines, as well as the N-alkyl derivatives obtained from 3-methylphenyl and 2-thienyl moieties. In addition to the presentation of a range of previously unreported data, it was also found that positional isomers of aryl methoxyl-substituted arylcyclohexylamines were readily distinguishable under a variety of analytical conditions. Copyright © 2015 John Wiley & Sons, Ltd.
Asunto(s)
Ciclohexilaminas/química , Drogas Ilícitas/química , Psicotrópicos/química , Alquilación , Cromatografía de Gases , Ciclohexilaminas/síntesis química , Humanos , Drogas Ilícitas/síntesis química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Metilación , Psicotrópicos/síntesis química , Detección de Abuso de Sustancias , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
An automated, continuous flow droplet screening system is presented, enabling real-time simultaneous solvent and continuous variable optimization. An optimal design of experiments strategy is applied to the alkylation of 1,2-diaminocyclohexane in 16 µL droplets, with scale-up demonstrated. Analysis of segmented flow results suggests correlation of yield with solvent hydrogen bond basicity.
Asunto(s)
Ensayos Analíticos de Alto Rendimiento/métodos , Técnicas Analíticas Microfluídicas/métodos , Alquilación , Ciclohexilaminas/síntesis química , Proyectos de Investigación , SolventesRESUMEN
The new C7N aminocyclitol kirkamide (1) was isolated from leaf nodules of the plant Psychotria kirkii by using a genome-driven (1)Hâ NMR-guided fractionation approach. The structure and absolute configuration were elucidated by HRMS, NMR, and single-crystal X-ray crystallography. An enantioselective total synthesis was developed, which delivered kirkamide (1) on a gram scale in 11â steps and features a Ferrier carbocyclization and a Pd-mediated hydroxymethylation. We propose that kirkamide is synthesized by Candidatus Burkholderia kirkii, the obligate leaf symbiont of Psychotria kirkii. Kirkamide (1) was shown to be toxic to aquatic arthropods and insects, thus suggesting that bacterial secondary metabolites play a protective role in the Psychotria/Burkholderia leaf nodule symbiosis.
Asunto(s)
Productos Biológicos/síntesis química , Ciclitoles/síntesis química , Ciclohexilaminas/síntesis química , Psychotria/química , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Burkholderia/fisiología , Cristalografía por Rayos X , Ciclitoles/química , Ciclitoles/aislamiento & purificación , Ciclohexilaminas/química , Ciclohexilaminas/aislamiento & purificación , Metilación , Modelos Moleculares , Paladio/química , Hojas de la Planta/química , Hojas de la Planta/microbiología , Psychotria/microbiología , SimbiosisRESUMEN
The gold(III) complexes of the type (1,2-diaminocyclohexane)(1,3-diaminopropane)gold(III) chloride, [(DACH)Au(pn)]Cl3, [where DACH = cis-, trans-1,2- and S,S-1,2-diaminocyclohexane and pn = 1,3-diaminopropane] have been synthesized and characterized using various spectroscopic and analytical techniques including elemental analysis, UV-Vis and FTIR spectroscopy; solution as well as solid-state NMR measurements. The solid-state (13)C NMR shows that 1,2-diaminocyclohexane (1,2-DACH) and 1,3-diaminopropane (pn) are strongly bound to the gold(III) center via N donor atoms. The stability of the mixed diamine ligand gold(III) was checked by UV-Vis spectroscopy and NMR measurements. The molecular structure of compound 1 (containing cis-1,2-DACH) was determined by X-ray diffraction analysis. The structure of 1 consists of [(cis-DACH)Au(pn)](3+) complex ion and chloride counter ions. Each gold atom in the complex ion adopts a distorted square-planar geometry. The structural details and relative stabilities of the four possible isomers of the complexes were also estimated at the B3LYP/LANL2DZ level of theoretical calculations. The computational study demonstrates that trans- conformations are slightly more stable than the cis- conformations. The antiproliferative effects and cytotoxic properties of the mixed ligand gold(III) complexes were evaluated in vitro on human gastric SGC7901 and prostate PC3 cancer cells using MTT assay. The antiproliferative study of the gold(III) complexes on PC3 and SGC7901 cells indicate that complex 3 (containing 1S,2S-(+)-1,2-(DACH)) is the most effective antiproliferative agent. The IC50 data reveal that the in vitro cytotoxicity of complex 3 against SGC7901 cancer cells manifested similar and very pronounced cytotoxic effects with respect to cisplatin. Moreover, the electrochemical behavior, and the interaction of complex 3 with two well-known model proteins, namely, hen egg white lysozyme and bovine serum albumin is also reported.
Asunto(s)
Complejos de Coordinación/química , Ciclohexilaminas/química , Diaminas/química , Oro/química , Animales , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Pollos , Cloruros/síntesis química , Cloruros/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Ciclohexilaminas/síntesis química , Diaminas/síntesis química , Oro/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Muramidasa/química , Albúmina Sérica Bovina/química , Rayos Ultravioleta , Difracción de Rayos XRESUMEN
The general translation initiation factor eIF2 is a major translational control point. Multiple signaling pathways in the integrated stress response phosphorylate eIF2 serine-51, inhibiting nucleotide exchange by eIF2B. ISRIB, a potent drug-like small molecule, renders cells insensitive to eIF2α phosphorylation and enhances cognitive function in rodents by blocking long-term depression. ISRIB was identified in a phenotypic cell-based screen, and its mechanism of action remained unknown. We now report that ISRIB is an activator of eIF2B. Our reporter-based shRNA screen revealed an eIF2B requirement for ISRIB activity. Our results define ISRIB as a symmetric molecule, show ISRIB-mediated stabilization of activated eIF2B dimers, and suggest that eIF2B4 (δ-subunit) contributes to the ISRIB binding site. We also developed new ISRIB analogs, improving its EC50 to 600 pM in cell culture. By modulating eIF2B function, ISRIB promises to be an invaluable tool in proof-of-principle studies aiming to ameliorate cognitive defects resulting from neurodegenerative diseases.