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1.
Nat Commun ; 12(1): 1644, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712595

RESUMEN

Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.


Asunto(s)
Pentanos/síntesis química , Aldehídos/química , Catálisis , Estructura Molecular , Estereoisomerismo
2.
Science ; 371(6536): 1313, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33766876
3.
Bioresour Technol ; 330: 125022, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33765631

RESUMEN

This work aims to synthesize S-(4-chlorophenyl)-(pyridin-2-yl) methanol (S-CPMA) in a green, economic, and efficient way. In the water-cyclohexane liquid-liquid system, recombinant Escherichia coli (E. coli) was used as a whole-cell catalyst and retained > 60% of its catalytic activity after five reuse cycles. In situ accumulation of the substrate/product in the organic phase effectively improves substrate tolerance and reduces product inhibition and toxicity. Meanwhile, a microreaction system consisting of membrane dispersion and three-dimensional (3D) bending-microchannel was developed to successfully generate droplet swarms with an average diameter of 30 µm. Large specific surface area provided high mass transfer efficiency between phases. While the analogous reaction in a traditional stirred tank required > 270 min to achieve a yield of > 99%, in this biphasic microreaction system, the yield reached 99.6% with a high enantiomeric excess (ee) of > 99% in only 80 min. Efficient synthesis was achieved by reducing the time by 70%.


Asunto(s)
Escherichia coli , Metanol , Biocatálisis , Estereoisomerismo
4.
Sci Total Environ ; 768: 144430, 2021 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-33736337

RESUMEN

Although hepatic metabolism of hexabromocyclododecanes (HBCDs) played critical roles in the selective bioaccumulation of HBCDs in humans, the hepatic metabolism patterns of its enantiomers remained ambiguous. Aiming to elucidate the mechanism on hepatic metabolism of hexabromocyclododecanes (HBCDs) enantiomers, the enantiomers ((+)-α-HBCD, (-)-α-HBCD, (+)-γ-HBCD, and (-)-γ-HBCD), the diastereoisomers (α-, ß-, and γ-HBCDs) and the mixed of α- and γ-HBCDs were incubated with human HepG2 cell under different exposure levels in the present study. The clearance percentages ranked as γ-HBCD enantiomers >ß-HBCD enantiomers >α-HBCD enantiomers at the same exposure levels. The clearance percentages of (+)- and (-)-α-HBCDs increased when cells were exposed to racemic α-HBCD and the mixture of racemic α- and γ-HBCDs (p < 0.05). (-)-γ-HBCD was more resistant to human hepatic metabolism than (+)-γ-HBCD, leading to the enantiomer fractions (EFs) of γ-HBCD lower than 0.50. (-)-α-HBCD was slightly more metabolized when independently exposed to α-HBCD, while (+)-α-HBCD was more preferentially metabolized after exposure to α- and γ-HBCD mixtures. Hydroxylation and debromination HBCD metabolites were identified. In addition, the different EFs of HBCDs in cells and mediums suggested the selective transfer of chiral HBCDs and HBCD metabolites through the cell membrane. This study provided new insight into the enantiomer-selective metabolism of HBCDs.


Asunto(s)
Retardadores de Llama , Hidrocarburos Bromados , Bioacumulación , Células Hep G2 , Humanos , Estereoisomerismo
5.
Molecules ; 26(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668491

RESUMEN

In this study, a complex consisting of 2-hydroxypropyl-ß-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin, (named dual chiral-achiral selector complex) was used for the determination of two novel potential anticancer agents of (I) and (II) aminoalkanol derivatives. This work aimed at developing an effective method that can be utilized for the determination of I (S), I (R), and II (S) and II (R) enantiomers of (I) and (II) compounds through the use of a dual chiral-achiral selector complex consisting of hydroxypropyl-ß-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin system by applying capillary electrophoresis. This combination proved to be beneficial in achieving high separation selectivity due to the combined effects of different modes of chiral discrimination. The enantiomers of (I) and (II) compounds were separated within a very short time of 3.6-7.2 min, in pH 2.5 phosphate buffer containing 2-hydroxypropyl-ß-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin system at a concentration of 5 and 10 mM, respectively, at 25 °C and +10 kV. The detection wavelength of the detector was set at 200 nm. The LOD for I (S), I (R), II (S), and II (R) was 65.2, 65.6, 65.1, and 65.7 ng/mL, respectively. LOQ for I (S), I (R), II (S), and II (R) was 216.5, 217.8, 217.1, and 218.1 ng/mL, respectively. Recovery was 94.9-99.9%. The repeatability and reproducibility of the method based on the values of the migration time, and the area under the peak was 0.3-2.9% RSD. The stability of the method was determined at 0.1-4.9% RSD. The developed method was used in the pilot studies for determining the enantiomers I (S), I (R), II (S), and II (R) in the blood serum.


Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/química , Aminas/aislamiento & purificación , Aminas/farmacología , Antineoplásicos/farmacología , Electroforesis Capilar , Porfirinas/química , Antineoplásicos/sangre , Tampones (Química) , Electrólitos/química , Concentración de Iones de Hidrógeno , Límite de Detección , Porfirinas/farmacología , Análisis de Regresión , Reproducibilidad de los Resultados , Estereoisomerismo , Temperatura
6.
Molecules ; 26(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33672044

RESUMEN

In spite of unique structural, spectroscopic and redox properties, the synthetic variants of the planar, antiaromatic hexaphyrin (1.0.1.0.1.0) derivatives 2, has been limited due to the low yields and difficulty in access to the starting material. A chemical modification of the meso-substituents could be good alternative overcoming the synthetic barrier. Herein, we report a regio-selective nucleophilic aromatic substitution (SNAr) of meso-pentafluorophenyl group in rosarrin 2 with catechol. The reaction afforded benzodioxane fused rosarrin 3 as single product with high yield. The intrinsic antiaromatic character of the starting rosarrin 2 retained throughout the reactions. Clean, two electron reduction was achieved by treatment of 3 with SnCl2•2H2O affording 26π-electron aromatic rosarrin 4. The synthesized compounds exhibited noticeable changes in photophysical and redox properties compared with starting rosarrin 2.


Asunto(s)
Porfirinas/química , Porfirinas/síntesis química , Técnicas Electroquímicas , Espectrofotometría Ultravioleta , Estereoisomerismo
7.
Carbohydr Polym ; 260: 117814, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712158

RESUMEN

Lytic polysaccharide monooxygenases (LPMOs), monocopper enzymes that oxidatively cleave recalcitrant polysaccharides, have important biotechnological applications. Thermothelomyces thermophilus is a rich source of biomass-active enzymes, including many members from auxiliary activities family 9 LPMOs. Here, we report biochemical and structural characterization of recombinant TtLPMO9H which oxidizes cellulose at the C1 and C4 positions and shows enhanced activity in light-driven catalysis assays. TtLPMO9H also shows activity against xyloglucan. The addition of TtLPMO9H to endoglucanases from four different glucoside hydrolase families (GH5, GH12, GH45 and GH7) revealed that the product formation was remarkably increased when TtLPMO9H was combined with GH7 endoglucanase. Finally, we determind the first low resolution small-angle X-ray scattering model of the two-domain TtLPMO9H in solution that shows relative positions of its two functional domains and a conformation of the linker peptide, which can be relevant for the catalytic oxidation of cellulose and xyloglucan.


Asunto(s)
Celulasas/metabolismo , Celulosa/metabolismo , Activación Enzimática/efectos de la radiación , Proteínas Fúngicas/metabolismo , Luz , Oxigenasas de Función Mixta/metabolismo , Sordariales/enzimología , Biomasa , Catálisis , Celulosa/química , Proteínas Fúngicas/química , Proteínas Fúngicas/clasificación , Proteínas Fúngicas/genética , Glucanos/química , Glucanos/metabolismo , Oxigenasas de Función Mixta/química , Oxigenasas de Función Mixta/clasificación , Oxigenasas de Función Mixta/genética , Oxidación-Reducción , Filogenia , Dominios Proteicos , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Dispersión del Ángulo Pequeño , Estereoisomerismo , Especificidad por Sustrato , Difracción de Rayos X , Xilanos/química , Xilanos/metabolismo
8.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669602

RESUMEN

Semiconductor single-walled carbon nanotubes (SWNTs) have unique characteristics owing to differences in the three-dimensional structure (chirality) expressed by the chiral index (n,m), and many studies on the redox characteristics of chirality have been reported. In this study, we investigated the relationship between the chirality of SWNTs and the oxidizing power of oxidants by measuring the near-infrared (NIR) absorption spectra of two double-stranded DNA-SWNT complexes with the addition of three oxidants with different oxidizing powers. A dispersion was prepared by mixing 0.5 mg of SWNT powder with 1 mg/mL of DNA solution. Different concentrations of hydrogen peroxide (H2O2), potassium hexachloroidylate (IV) (K2IrCl6), or potassium permanganate (KMnO4) were added to the dispersion to induce oxidation. Thereafter, a catechin solution was added to observe if the absorbance of the oxidized dispersion was restored by the reducing action of the catechin. We found that the difference in the oxidizing power had a significant effect on the detection sensitivity of the chiralities of the SWNTs. Furthermore, we revealed a detectable range of oxidants with different oxidizing powers for each chirality.


Asunto(s)
Nanotubos de Carbono/química , Fenómenos Ópticos , Oxidantes/química , ADN/química , Rayos Infrarrojos , Oxidación-Reducción , Estereoisomerismo
9.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670764

RESUMEN

Phytochemical investigation of leaves and stembark of Artocarpus lacucha collected in Thailand resulted in three yet undescribed isomeric flavan-3-ol derivatives (1-3), the four known compounds gambircatechol (4), (+)-catechin (5), (+)-afzelechin (6) and the stilbene oxyresveratrol (7). Compounds 1 to 3 feature 6/6/5/6/5/6 core structures. All structures were deduced by NMR and MS, while density functional theory (DFT) calculations on B3LYP theory level were performed of compounds 1 to 3 to support the stereochemistry in positions 2 and 3 in the C-ring. Possible biosynthetic pathways leading to 4 are discussed. The DPPH assay revealed high radical scavenging activities for 1 (EC50 = 9.4 ± 1.0 µmol mL-1), 2 (12.2 ± 1.1), 3 (10.0 ± 1.5) and 4 (19.0 ± 2.6), remarkably lower than ascorbic acid (EC50 = 34.9) and α-tocopherol (EC50 = 48.6). A cytotoxicity assay revealed moderate but consistent antiproliferative properties of 1 in CH1/PA-1 (ovarian teratocarcinoma) and SW480 (colon carcinoma) cells, with IC50 values of 25 ± 6 and 34 ± 4 µM, respectively, whereas effects in A549 (non-small cell lung cancer) cells were rather negligible. The performed DCFH-DA assay of 1 in the former cell lines confirmed potent antioxidative effects even in the cellular environment.


Asunto(s)
Artocarpus/química , Flavonoides/farmacología , Depuradores de Radicales Libres/farmacología , Antioxidantes/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Flavonoides/química , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Oxidación-Reducción , Estereoisomerismo
10.
Molecules ; 26(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673047

RESUMEN

The analysis of stability of biologically active compounds requires an accurate determination of their structure. We have found that 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles are generally unstable in the presence of acids and bases and are rearranged into the salts of spiropyrazolinium compounds. Hence, there is a significant probability that it is the rearranged products that should be attributed to biological activity and not the primarily screened 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles. A series of the 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium (spiropyrazoline) benzoates and chloride was synthesized by Boulton-Katritzky rearrangement of 5-substituted phenyl-3-[2-(morpholin-1-yl)ethyl]-1,2,4-oxadiazoles and characterized using FT-IR and NMR spectroscopy and X-ray diffraction. Spiropyrazolylammonium chloride demonstrates in vitro antitubercular activity on DS (drug-sensitive) and MDR (multidrug-resistant) of MTB (M. tuberculosis) strains (1 and 2 µg/mL, accordingly) equal to the activity of the basic antitubercular drug rifampicin; spiropyrazoline benzoates exhibit an average antitubercular activity of 10-100 µg/mL on MTB strains. Molecular docking studies revealed a series of M. tuberculosis receptors with the energies of ligand-receptor complexes (-35.8--42.8 kcal/mol) close to the value of intermolecular pairwise interactions of the same cation in the crystal of spiropyrazolylammonium chloride (-35.3 kcal/mol). However, only in complex with transcriptional repressor EthR2, both stereoisomers of the cation realize similar intermolecular interactions.


Asunto(s)
Antituberculosos/química , Benzoatos/química , Oxadiazoles/química , Tuberculosis/tratamiento farmacológico , Antituberculosos/farmacología , Benzoatos/farmacología , Cloruros/química , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Oxadiazoles/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Estereoisomerismo , Relación Estructura-Actividad , Tuberculosis/microbiología
11.
Molecules ; 26(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33669919

RESUMEN

With the rapid development of global industry and increasingly frequent product circulation, the separation and detection of chiral drugs/pesticides are becoming increasingly important. The chiral nature of substances can result in harm to the human body, and the selective endocrine-disrupting effect of drug enantiomers is caused by differential enantiospecific binding to receptors. This review is devoted to the specific recognition and resolution of chiral molecules by chromatography and membrane-based enantioseparation techniques. Chromatographic enantiomer separations with chiral stationary phase (CSP)-based columns and membrane-based enantiomer filtration are detailed. In addition, the unique properties of these chiral resolution methods have been summarized for practical applications in the chemistry, environment, biology, medicine, and food industries. We further discussed the recognition mechanism in analytical enantioseparations and analyzed recent developments and future prospects of chromatographic and membrane-based enantioseparations.


Asunto(s)
Plaguicidas/aislamiento & purificación , Preparaciones Farmacéuticas/aislamiento & purificación , Fraccionamiento Químico , Cromatografía , Plaguicidas/química , Preparaciones Farmacéuticas/química , Estereoisomerismo
12.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671806

RESUMEN

The metabolism of brassinosteroid leads to structural modifications in the ring skeleton or the side alkyl chain. The esterification and glycosylation at C-3 are the most common metabolic pathways, and it has been suggested that conjugate brassinosteroids are less active or inactive. In this way, plants regulate the content of active brassinosteroids. In this work, the synthesis of brassinosteroid 24-norcholane type analogs conjugated at C-3 with benzoate groups, carrying electron donor and electron attractant substituents on the aromatic ring, is described. Additionally, their growth-promoting activities were evaluated using the Rice Lamina Inclination Test (RLIT) and compared with that exhibited by brassinolide (used as positive control) and non-conjugated analogs. The results indicate that at the lowest tested concentrations (10-8-10-7 M), all analogs conjugated at C-3 exhibit similar or higher activities than brassinolide, and the diasteroisomers with S configuration at C-22 are the more active ones. Increasing concentration (10-6 M) reduces the biological activities of analogs as compared to brassinolide.


Asunto(s)
Benzoatos/química , Brasinoesteroides/síntesis química , Oryza/efectos de los fármacos , Reguladores del Crecimiento de las Plantas/síntesis química , Benzoatos/farmacología , Brasinoesteroides/química , Brasinoesteroides/farmacología , Relación Dosis-Respuesta a Droga , Conformación Molecular , Oryza/metabolismo , Reguladores del Crecimiento de las Plantas/química , Reguladores del Crecimiento de las Plantas/farmacología , Estereoisomerismo
13.
Molecules ; 26(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672444

RESUMEN

Regioselective synthesis of novel 2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives has been developed by annulation reactions of 8-quinolinesulfenyl halides with vinyl chalcogenides (vinyl ethers, divinyl sulfide, divinyl selenide and phenyl vinyl sulfide) and tetravinyl silane. The novel reagent 8-quinolinesulfenyl bromide was used in the annulation reactions. The influence of the substrate structure and the nature of heteroatoms on the direction of the reactions and on product yields has been studied. The opposite regiochemistry was observed in the reactions with vinyl chalcogenides and tetravinyl silane. The obtained condensed heterocycles are novel water-soluble functionalized compounds with promising biological activity.


Asunto(s)
Compuestos de Quinolinio/síntesis química , Estructura Molecular , Compuestos de Quinolinio/química , Solubilidad , Estereoisomerismo , Agua/química
14.
Molecules ; 26(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672731

RESUMEN

Despite significant interest, the chiroptical properties of subporphyrins have rarely been investigated because chiral subporphyrins are elusive. Here, inherently chiral subporphyrins are elaborated by forming a fused pyran ring at the periphery of an A2B-type meso-aryl-substituted subporphyrin. Their circular dichroism (CD) properties are largely affected by the peripheral substituents and the dihedral angles between the meso-aryl substituents and the subporphyrin core: the ß-perbromo subporphyrin with an orthogonal arrangement of the meso-phenyl substituents to the subporphyrin core exhibits weak CD signals corresponding to the Q bands, whereas the unsubstituted species with smaller dihedral angles shows relatively intense CD signals. A detailed structure-property relationship of these chiral subporphyrins was elucidated by time-dependent (TD) DFT calculations. This study reveals that the CD properties of chiral subporphyrins can be controlled by peripheral substitution and meso-aryl substituents.


Asunto(s)
Compuestos de Boro/química , Porfirinas/química , Compuestos de Boro/síntesis química , Dicroismo Circular , Teoría Funcional de la Densidad , Conformación Molecular , Estereoisomerismo
15.
J Chromatogr A ; 1641: 461992, 2021 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-33706165

RESUMEN

Stereoisomeric determination of individual triacylglycerols (TAGs) in natural oils and fats is a challenge due to similar physicochemical properties of TAGs with different fatty acid combinations. In this study, we present a strategy to resolve the enantiomeric composition of nutritionally important TAGs in sea buckthorn (Hippophaë rhamnoides) as an example food matrix. The targeted strategy combines 1) fatty acid profiling with GC, 2) separation of TAGs with RP-HPLC, 3) stereospecific separation with chiral-phase HPLC and 4) structural characterization with MS. Three major asymmetric diacid- and triacid-TAG species were analyzed in sea buckthorn pulp oil. Off-line coupling of RP-HPLC and chiral-phase HPLC allowed separation of several TAG regioisomers and enantiomers, which could not be resolved using one-dimensional techniques. Enantiomeric ratios were determined and specific structural analysis of separated TAGs was performed using direct inlet ammonia negative ion chemical ionization method. Of the TAG 16:0/16:1/16:1 palmitic acid (C16:0) was located predominantly in a primary position and the enantiomeric ratio of TAG sn-16:1-16:1-16:0 to sn-16:0-16:1-16:1 was 70.5/29.5. Among the TAGs 16:0/16:0/18:2 and 16:0/16:0/16:1, only ca 5% had C16:0 in the sn-2 position, thus, ca 95% were symmetric sn-16:0-18:2-16:0 and sn-16:0-16:1-16:0. The enantiomeric ratio of triacid-TAGs containing C16:0 and two unsaturated fatty acids (palmitoleic C16:1, oleic C18:1 or linoleic acids C18:2) could not be resolved due to lack of commercial enantiopure reference compounds. However, it became clear that the targeted strategy presented offer unique and convenient method to study the enantiomeric structure of individual TAGs.


Asunto(s)
Cromatografía/métodos , Espectrometría de Masas/métodos , Triglicéridos/química , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa , Ácidos Grasos/análisis , Hippophae/química , Aceites/análisis , Estereoisomerismo
16.
Sci Total Environ ; 771: 144831, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33548698

RESUMEN

Cyflumetofen (CYF) is a novel chiral acaricide widely used in commercial crops to control mites. The environmental risks exposed by CYF in the soil, especially at the enantiomer level, remain unclear. We found that the (+)-CYF enantiomer was preferentially degraded in acid-soil, resulting in (-)-CYF enrichment. 16S rRNA and qPCR analysis indicated that decreased bacterial abundance by 12.79-61.80% and 2.52-52.48% in (-)-CYF treatment and (+)-CYF treatment, respectively. Diversity was also decreased with (-)-CYF treatment. Interestingly, several beneficial bacteria, for instance, Alphaproteobacteria (class), Sphingomonadaceae (family), and Arthrobacter (specise) were more enriched following (-)-CYF. The abundance of N2-fixing bacteria showed a sustained reduction with time, and the decrease was 3.24-72.94% with (-)-CYF and 25.37-73.11% with (+)-CYF treatment. Compared with the (+)-CYF treatment could positively promote nitrification, while the treatment (-)-CYF significantly reduced the abundance of amoA gene; namely it significantly negatively affected the nitrification in the nitrogen cycle. Through our further research, we found that Actinobacteria, Alphaproteobacteria, Lysobacter; Sphingomonas, Patescibacteria, Saccharimonadia, and Saccharimonadales showed synergistic effects with the nitrogen cycling-related genes nifH and amoA. These results contribute to a comprehensive environmental risk assessment of CYF in acid-soil at the enantiomer level.


Asunto(s)
Microbiota , Suelo , Archaea/genética , Nitrificación , Nitrógeno , Ciclo del Nitrógeno , Propionatos , ARN Ribosómico 16S/genética , Microbiología del Suelo , Estereoisomerismo
17.
Science ; 371(6530): 702-707, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33574208

RESUMEN

We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer. Two different CPA scaffolds have proven to be essential for achieving stereodivergence: peptide-embedded phosphothreonine-derived CPAs, which reinforce and amplify the inherent substrate preference, and C2-symmetric BINOL-derived CPAs, which completely overturn this stereochemical preference. The presently reported catalytic method does not require stoichiometric activators or chiral auxiliaries and enables asymmetric catalysis with readily available phosphoramidites. The method was applied to the stereocontrolled synthesis of diastereomeric dinucleotides as well as cyclic dinucleotides, which are of broad interest in immuno-oncology as agonists of the stimulator of interferon genes (STING) pathway.


Asunto(s)
Nucleótidos Cíclicos/síntesis química , Oligonucleótidos/síntesis química , Catálisis , Estructura Molecular , Nucleótidos Cíclicos/química , Oligonucleótidos/química , Compuestos Organofosforados/química , Ácidos Fosfóricos/química , Oligonucleótidos Fosforotioatos/química , Estereoisomerismo
18.
J Chromatogr A ; 1639: 461919, 2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33535114

RESUMEN

The first CE methodology enabling the enantiomeric separation of panthenol was developed in this work. Electrokinetic chromatography with cyclodextrins (CD-EKC) was the CE mode employed for this purpose. The effect of different experimental variables such as the nature and concentration of the cyclodextrin, the temperature and the separation voltage was investigated. The best enantiomeric separation was obtained with 25 mM (2-carboxyethyl)-ß-CD (CE-ß-CD) in 100 mM borate buffer (pH 9.0), with a separation voltage of 30 kV and a temperature of 30 °C. Under these conditions, an enantiomeric resolution of 2.0 in an analysis time of 4.2 min was obtained, being the biologically active enantiomer d-panthenol (dexpanthenol) the second-migrating enantiomer. The analytical characteristics of the method were evaluated in terms of precision, accuracy, selectivity, linearity, LOD, and LOQ, showing a good performance for the quantitation of dexpanthenol in cosmetic and pharmaceutical formulations. The enantiomeric impurity (L-panthenol) could be detected at a 0.1% level with respect to the majority enantiomer, allowing to accomplish the requirements of the ICH guidelines. The method was also successfully applied to study the stability of panthenol under abiotic and biotic conditions and its toxicity on non-target organisms (the aquatic plant Spirodela polyrhiza).


Asunto(s)
Electroforesis Capilar/métodos , Ácido Pantoténico/análogos & derivados , Pruebas de Toxicidad , Araceae/efectos de los fármacos , Cromatografía , Cosméticos/análisis , Ciclodextrinas/química , Límite de Detección , Ácido Pantoténico/química , Ácido Pantoténico/aislamiento & purificación , Ácido Pantoténico/toxicidad , Preparaciones Farmacéuticas/análisis , Estereoisomerismo
19.
Nucleic Acids Res ; 49(4): 2317-2332, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33524154

RESUMEN

We recently showed that Saccharomyces cerevisiae telomeric DNA can fold into an unprecedented pseudocircular G-hairpin (PGH) structure. However, the formation of PGHs in the context of extended sequences, which is a prerequisite for their function in vivo and their applications in biotechnology, has not been elucidated. Here, we show that despite its 'circular' nature, PGHs tolerate single-stranded (ss) protrusions. High-resolution NMR structure of a novel member of PGH family reveals the atomistic details on a junction between ssDNA and PGH unit. Identification of new sequences capable of folding into one of the two forms of PGH helped in defining minimal sequence requirements for their formation. Our time-resolved NMR data indicate a possibility that PGHs fold via a complex kinetic partitioning mechanism and suggests the existence of K+ ion-dependent PGH folding intermediates. The data not only provide an explanation of cation-type-dependent formation of PGHs, but also explain the unusually large hysteresis between PGH melting and annealing noted in our previous study. Our findings have important implications for DNA biology and nanotechnology. Overrepresentation of sequences able to form PGHs in the evolutionary-conserved regions of the human genome implies their functionally important biological role(s).


Asunto(s)
ADN Circular/química , Emparejamiento Base , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Conformación de Ácido Nucleico , Motivos de Nucleótidos , Saccharomyces cerevisiae/genética , Estereoisomerismo , Telómero/química
20.
Nat Commun ; 12(1): 847, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558503

RESUMEN

A large G4C2-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders.


Asunto(s)
Proteína C9orf72/genética , Expansión de las Repeticiones de ADN/genética , Mutación/genética , Oligonucleótidos/química , Oligonucleótidos/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Proteína C9orf72/química , Exones/genética , Glutamatos/toxicidad , Intrones/genética , Ratones , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/patología , Empalme del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estereoisomerismo
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