RESUMEN
N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.
Asunto(s)
Antineoplásicos , Etilenos , Compuestos Heterocíclicos , Cetonas , Humanos , Línea Celular Tumoral , Etilenos/química , Etilenos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Relación Estructura-Actividad , Histona Desacetilasas/metabolismo , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Acetales/química , Acetales/farmacología , Acetales/síntesis química , Proteínas RepresorasRESUMEN
Nitrones are widely used as 1,3-dipoles in organic synthesis, but control of their reactions is not always easy. This review outlines our efforts to make the reactions of nitrones more predictable and easier to use. These efforts can be categorized into (1) 1,3-nucleophilic addition reaction of ketene silyl acetals to nitrones, (2) geometry-controlled cycloaddition of C-alkoxycarbonyl nitrones, (3) stereo-controlled cycloaddition using double asymmetric induction, and (4) generation of nitrones by N-selective modification of oximes.
Asunto(s)
Óxidos de Nitrógeno , Óxidos de Nitrógeno/química , Óxidos de Nitrógeno/síntesis química , Reacción de Cicloadición , Estructura Molecular , Acetales/química , Acetales/síntesis química , Cetonas/química , Cetonas/síntesis química , Oximas/química , Oximas/síntesis química , Etilenos/química , EstereoisomerismoRESUMEN
Fluorescent probes with outstanding physical and biological properties are superior for functional fluorescent dyes design. However, few studies pay attention to the stability of specific groups in fluorescent probes. The aldehyde group in the fluorescent probe is highly active but unstable under certain conditions. Therefore, we introduced ethoxy groups to realize the conversion to aldehyde groups under acidic conditions and avoid the instability of straightforward aldehyde groups. In this work, two fluorophores based on the multi acetal difluoroboraindacene (BODIPY) units with combination of the pharmaceutical intermediate chalcone have been firstly developed. In the design part, chalcone was introduced as a medium for fluorophore and multiple acetal. The mild synthesis strategy is based on the ligand ((Z)-2-chloro-1-(difluoroboranyl)-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl)methyl)-1H-pyrrole) and connects with chalcone in (2E,2'E)-3,3'-(1,3-phenylene)bis(1-(2,4-bis(2,2-diethoxyethoxy)phenyl)prop-2-en-1-one). The emission wavelengths of the products are around 530 nm with high fluorescence intensity. To highlight the biological characteristics of these novel BODIPY fluorescents, we further demonstrated biological analysis studies on MTT and flow cytometry assays. The IC50 values of BODIPY 5 ranged from 79 ± 6.11 to 63 ± 5.67 µM and BODIPY 6 were found to be 86 ± 4.07 to 58 ± 10.51 µM in tested cell lines. Flow cytometry data analysis shows that the representative agent 6 and reference have similar rational apoptosis rates in first quadrant. Last but not least, 6 shows outstanding biological compatibility and cell imaging potential in live cell imaging and in vivo assay, not only is the fluorescence prominent enough, but also rapidly distributes. Thus, our study reports a mild synthesis strategy and full biological analysis on BODIPY fluorescents, and the subtle modulation of the physical and biological properties by pharmaceutical substituents makes these designed chalcone-BODIPY-based dyes hopeful to realize drug functional fluorescent dyes. Two new highly sensitive BODIPY fluorophores are synthesized based on the ligand ((Z)-2-chloro-1-(difluoroboranyl)-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl)methyl)-1H-pyrrole), which connects with chalcone in (2E,2'E)-3,3'-(1,3/4-phenylene)bis(1-(2,4-bis(2,2-diethoxyethoxy)phenyl)prop-2-en-1-one). Multiple acetals were introduced and the physical and biological properties of BODIPYs are described with MTT assay and in vitro and in vivo imaging.
Asunto(s)
Acetales/química , Compuestos de Boro/química , Chalconas/química , Colorantes Fluorescentes/química , Acetales/síntesis química , Animales , Apoptosis , Compuestos de Boro/síntesis química , Chalconas/síntesis química , Citometría de Flujo , Colorantes Fluorescentes/síntesis química , Células HCT116 , Células HeLa , Humanos , Ratones , Imagen ÓpticaRESUMEN
A straightforward and scalable method for the synthesis of protected 2-hydroxyglycals is described. The approach is based on the chlorination of carbohydrate-derived hemiacetals, followed by an elimination reaction to establish the glycal moiety. 1,2-dehydrochlorination reactions were studied on a range of glycosyl chlorides to provide suitable reaction conditions for this transformation. Benzyl ether, isopropylidene and benzylidene protecting groups, as well as interglycosidic linkage, were found to be compatible with this protocol. The described method is operationally simple and allows for the quick preparation of 2-hydroxyglycals with other than ester protecting groups, providing a feasible alternative to existing methods.
Asunto(s)
Acetales/química , Acetales/síntesis química , Halogenación , Alquenos/química , Técnicas de Química Sintética , Éteres/química , GlicosilaciónRESUMEN
Readily available 1,2-amino alcohols provide the framework for a new generation of chiral carboxylic acid catalysts that rival the acidity of the widely used chiral phosphoric acid catalyst (S)-TRIP. Covalently linked thiourea sites stabilize the carboxylate conjugate bases of these catalysts via anion-binding, an interaction that is largely responsible for the low pKa values. The utility of the new catalysts is illustrated in the context of challenging [4 + 2] cycloadditions of salicylaldehyde-derived acetals with homoallylic and bishomoallylic alcohols, providing polycyclic chromanes in a highly enantioselective fashion.
Asunto(s)
Acetales/síntesis química , Ácidos Carboxílicos/química , Acetales/química , Catálisis , Reacción de Cicloadición , Estructura MolecularRESUMEN
Aldehyde is one of most synthetically versatile functional groups and can participate in numerous chemical transformations. While a variety of simple aromatic aldehydes are commercially available, those with a more complex substitution pattern are often difficult to obtain. Benzylic oxygenation of methylarenes is a highly attractive method for aldehyde synthesis as the starting materials are easy to obtain and handle. However, regioselective oxidation of functionalized methylarenes, especially those that contain heterocyclic moieties, to aromatic aldehydes remains a significant challenge. Here we show an efficient electrochemical method that achieves site-selective electrooxidation of methyl benzoheterocycles to aromatic acetals without using chemical oxidants or transition-metal catalysts. The acetals can be converted to the corresponding aldehydes through hydrolysis in one-pot or in a separate step. The synthetic utility of our method is highlighted by its application to the efficient preparation of the antihypertensive drug telmisartan.
Asunto(s)
Acetales/química , Aldehídos/química , Técnicas Electroquímicas/métodos , Hidrocarburos Aromáticos/química , Modelos Químicos , Acetales/síntesis química , Aldehídos/síntesis química , Amidinas/química , Bencimidazoles/química , Catálisis , Hidrocarburos Aromáticos/síntesis química , Hidrólisis , Estructura Molecular , Oxidantes/química , Oxidación-ReducciónRESUMEN
BACKGROUND: Hafnium(IV) tetrachloride efficiently catalyzes the protection of a variety of aldehydes and ketones, including benzophenone, acetophenone, and cyclohexanone, to the corresponding dimethyl acetals and 1,3-dioxolanes, under microwave heating. Substrates possessing acid-labile protecting groups (TBDPS and Boc) chemoselectively generated the corresponding acetal/ketal in excellent yields. AIMS AND OBJECTIVES: In this study. the selective protection of aldehydes and ketones using a Hafnium(IV) chloride, which is a novel catalyst, under microwave heating was observed. Hence, it is imperative to find suitable conditions to promote the protection reaction in high yields and short reaction times. This study was undertaken not only to find a novel catalyst but also to perform the reaction with substrates bearing acid-labile protecting groups, and study the more challenging ketones as benzophenone. MATERIALS AND METHODS: Using a microwave synthesis reactor Monowave 400 of Anton Paar, the protection reaction was performed on a raging temperature of 100°C ±1, a pressure of 2.9 bar, and an electric power of 50 W. More than 40 substrates have been screened and protected, not only the aldehydes were protected in high yields but also the more challenging ketones such as benzophenone were protected. All the products were purified by simple flash column chromatography, using silica gel and hexanes/ethyl acetate (90:10) as eluents. Finally, the protected substrates were characterized by NMR 1H, 13C and APCI-HRMS-QTOF. RESULTS: Preliminary screening allowed us to find that 5 mol % of the catalyst is enough to furnish the protected aldehyde or ketone in up to 99% yield. Also it was found that substrates with a variety of substitutions on the aromatic ring (aldehyde or ketone), that include electron-withdrawing and electrondonating group, can be protected using this methodology in high yields. The more challenging cyclic ketones were also protected in up to 86% yield. It was found that trimethyl orthoformate is a very good additive to obtain the protected acetophenone. Finally, the protection of aldehydes with sensitive functional groups was performed. Indeed, it was found that substrates bearing acid labile groups such as Boc and TBDPS, chemoselectively generated the corresponding acetal/ketal compound while keeping the protective groups intact in up to 73% yield. CONCLUSION: Hafnium(IV) chloride as a catalyst provides a simple, highly efficient, and general chemoselective methodology for the protection of a variety of structurally diverse aldehydes and ketones. The major advantages offered by this method are: high yields, low catalyst loading, air-stability, and non-toxicity.
Asunto(s)
Acetales/síntesis química , Aldehídos/química , Hafnio/química , Cetonas/química , Catálisis , Calefacción , MicroondasRESUMEN
Enantioselectivity increases with increasing carbonyl electrophilicity in 2-propanol-mediated reductive couplings of aldehydes with branched aryl-substituted allylic acetates to form products of carbonyl anti-(α-aryl)allylation. This unusual phenomenon is caused by aldehyde coordination to diastereomeric kinetic vs thermodynamic carbonyl binding sites that deliver enantiomeric products. Exploiting this effect, anti-diastereo- and enantioselective (α-aryl)allylations of fluoral hydrate and difluoroacetaldehyde ethyl hemiacetal were developed.
Asunto(s)
Acetaldehído/análogos & derivados , Acetales/síntesis química , Compuestos Alílicos/síntesis química , Derivados de Atropina/síntesis química , Iridio/química , 2-Propanol/química , Acetaldehído/química , Acetatos/química , Catálisis , Cinética , Oxidación-Reducción , Estereoisomerismo , TermodinámicaRESUMEN
A series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50â¯=â¯248.6⯵g/mL) and curative activity against potato virus Y (EC50â¯=â¯350.5⯵g/mL), which were better than those of ningnanmycin (357.7⯵g/mL and 493.7⯵g/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity.
Asunto(s)
Antivirales/farmacología , Cucumovirus/efectos de los fármacos , Nicotiana/virología , Enfermedades de las Plantas/prevención & control , Potyvirus/efectos de los fármacos , Quinazolinas/farmacología , Acetales/síntesis química , Acetales/química , Acetales/farmacología , Antivirales/síntesis química , Antivirales/química , Resistencia a la Enfermedad/efectos de los fármacos , Diseño de Fármacos , Enfermedades de las Plantas/virología , Quinazolinas/síntesis química , Quinazolinas/químicaRESUMEN
C(sp3)-H bond functionalization has emerged as a robust tool enabling rapid construction of molecular complexity from simple building blocks, and the development of asymmetric versions of this reaction creates a powerful methodology to access enantiopure sp3-rich materials. Herein, we report the stereoselective functionalization of C(sp3)-H bonds of cyclic ethers employing a photochemically active diaryliodonium salt in combination with an anionic phase-transfer catalyst. The synthetic strategy outlined herein allows for regio- and stereochemical control in the α-C-H acetalization of furans and pyrans using alcohol nucleophiles, thus providing the ability to control the configuration at the stereogenic exocyclic acetal carbon.
Asunto(s)
Acetales/síntesis química , Éteres Cíclicos/química , Luz , Compuestos Onio/química , Fosfatos/química , Acetales/química , Furanos/química , Estructura Molecular , Piranos/química , EstereoisomerismoRESUMEN
Spiromamakone A is a racemic natural product having a naphthyl acetal group on a spiro[4,4]nonadiene skeleton. Its total synthesis was achieved by double oxa-Michael addition of 1,8-dihydroxynaphthalene to 2-(1-bromoalkylidene)-4-isopropoxy-4-cyclopentene-1,3-dione, which was prepared by palladium(II)-catalyzed ring expansion of 4-(1-alkynyl)-4-hydroxy-3-isopropoxy-2-cyclobuten-1-one, and a subsequent intramolecular aldol reaction. The synthesis using optically active intermediates enabled identification of the racemization step of spiromamakone A and revealed that spiromamakone A and spiropreussione A are identical; the latter had been reported as a constitutional isomer of the other.
Asunto(s)
Acetales/química , Naftalenos/química , Compuestos de Espiro/química , Acetales/síntesis química , Técnicas de Química Sintética , Modelos Moleculares , Conformación Molecular , Naftalenos/síntesis química , Compuestos de Espiro/síntesis químicaRESUMEN
Reported is the first enantioselective oxidative Pummerer-type transformation using phase-transfer catalysis to deliver enantioenriched sulfur-bearing heterocycles. This reaction includes the direct oxidation of sulfides to a thionium intermediate, followed by an asymmetric intramolecular nucleophilic addition to form chiral cyclic N,S-acetals with moderate to high enantioselectivites. Deuterium-labelling experiments were performed to identify the stereodiscrimination step of this process. Further analysis of the reaction transition states, by means of multidimensional correlations and DFT calculations, highlight the existence of a set of weak noncovalent interactions between the catalyst and substrate that govern the enantioselectivity of the reaction.
Asunto(s)
Acetales/síntesis química , Catálisis , Ciclización , Oxidación-Reducción , Transición de Fase , Estereoisomerismo , Especificidad por Sustrato , Sulfuros/química , Azufre/químicaRESUMEN
Polymer masked-unmasked protein therapy (PUMPT) employs polymer conjugation to protect therapeutic proteins during transit through the bloodstream and allow controlled release at a disease site via triggered degradation of the polymeric component. Most reported PUMPT systems are based on the specific enzymatic degradation of the polymeric component to release the protein and reinstate its activity. In these cases, therapeutic output is dependent on the presence of the required enzyme at the disease site at a sufficiently high concentration. The present study aims to overcome this design limitation by using pH as the protein release trigger. An acidic-pH triggered PUMPT system is described herein employing biodegradable polyacetals (PAs) and trypsin as a model protein. While this system protects trypsin activity at the neutral pH of the bloodstream, acidic pH (characteristic of disease sites, tissue damage, or lysosomal compartments) contributes to PA degradation and the "unmasking" of protein activity.
Asunto(s)
Acetales/síntesis química , Sistemas de Liberación de Medicamentos , Polímeros/síntesis química , Proteínas/síntesis química , Acetales/química , Acetales/farmacología , Línea Celular Tumoral , Liberación de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Neoplasias/tratamiento farmacológico , Polímeros/química , Polímeros/farmacología , Proteínas/química , Proteínas/farmacología , Tripsina/síntesis química , Tripsina/química , Tripsina/farmacologíaRESUMEN
The synthesis of a fully degradable, bio-based, sustained release, pro-antimicrobial polymer network comprised of degradable acetals (PANDA) is reported. The active antimicrobial agent - p-anisaldehyde (pA) (an extract from star anise) - was converted into a UV curable acetal containing pro-antimicrobial monomer and subsequently photopolymerized into a homogenous thiol-ene network. Under neutral to acidic conditions (pHâ¯<â¯8), the PANDAs undergo surface erosion and exhibit sustained release of pA over 38â¯days. The release of pA from PANDAs was shown to be effective against both bacterial and fungal pathogens. From a combination of confocal microscopy and transmission electron microscopy, we observed that the released pA disrupts the cell membrane. Additionally, we demonstrated that PANDAs have minimal cytotoxicity towards both epithelial cells and macrophages. Although a model platform, these results point to promising pathways for the design of fully degradable sustained-release antimicrobial systems with potential applications in agriculture, pharmaceuticals, cosmetics, household/personal care, and food industries. STATEMENT OF SIGNIFICANCE: With the increasing number of patients prescribed immunosuppressants coupled with the rise in antibiotic resistance - life-threatening microbial infections are a looming global threat. With limited success within the antibiotic pipeline, nature-based essential oils (EOs) are being investigated for their multimodal effectiveness against microbes. Despite the promising potential of EOs, difficulties in their encapsulation, limited water solubility, and high volatility limit their use. Various studies have shown that covalent attachment of these EO derivatives to polymers can mitigate these limitations. The current study presents the synthesis of a fully-degradable, sustained release, cytocompatible, pro-antimicrobial acetal network derived from p-anisaldehyde. This polymer network design provides a pathway toward application-specific EO releasing materials with quantitative encapsulation efficiencies, sustained release, and broad-spectrum antimicrobial activity.
Asunto(s)
Acetales/síntesis química , Antiinfecciosos/síntesis química , Materiales Biocompatibles/síntesis química , Polímeros/síntesis química , Acetales/química , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antifúngicos/farmacología , Bacterias/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Muerte Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Chlorocebus aethiops , Hongos/efectos de los fármacos , Cinética , Ratones , Pruebas de Sensibilidad Microbiana , Polímeros/química , Células RAW 264.7 , Células VeroRESUMEN
A fluorinated cobalt(III) porphyrin complex [Co(TPFPP)NTf2·2C2H5OH, where TPFPP=5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, Tf=CF3SO2] promotes hydroalkoxylation of alkynes to give acetals in good to excellent yields. The acetals can be directly functionalized with nucleophiles in a one-pot procedure.
Asunto(s)
Acetales/síntesis química , Alquinos/química , Cobalto/química , Metaloporfirinas/química , Acetales/química , Halogenación , Modelos Moleculares , Estructura MolecularRESUMEN
XtalFluor-E® has been extensively used in a broad range of reactions in the past few years. Here we report its use with protic nucleophiles in a catalytic manner for the in situ generation of protons that lead to the proto-functionalization of activated olefins. Utilizing the latter protocol, proto etherification of enamides gives rise to N,O-acetals in nearly quantitative yields.
Asunto(s)
Acetales/síntesis química , Amidas/química , Hidrocarburos Fluorados/química , Compuestos de Azufre/química , Acetales/química , Estructura Molecular , ProtonesRESUMEN
Dysprosium(III) trifluoromethanesulfonate-catalyzed per-O-acetylation and regioselective anomeric de-O-acetylation of carbohydrates can be tuned by adjusting the reaction medium. In this study, the per-O-acetylation of unprotected sugars by using a near-stoichiometric amount of acetic anhydride under solvent-free conditions resulted in the exclusive formation of acetylated saccharides as anomeric mixtures, whereas anomeric de-O-acetylation in methanol resulted in a moderate-to-excellent yield. Reactions with various unprotected monosaccharides or disaccharides followed by a semi-one-pot sequential conversion into the corresponding acetylated glycosyl hemiacetal also resulted in high yields. Furthermore, the obtained hemiacetals could be successfully transformed into trichloroimidates after Dy(OTf)3 -catalyzed glycosylation.
Asunto(s)
Acetales/síntesis química , Carbohidratos/química , Disprosio/química , Mesilatos/química , Compuestos Organometálicos/química , Acetales/química , Acetilación , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Taking advantage of the structural similarity between aspartic proteases, small-molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC50 in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Peptidomiméticos/química , Peptidomiméticos/farmacología , Acetales/síntesis química , Acetales/química , Acetales/farmacología , Secuencia de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/química , Ácido Aspártico Endopeptidasas/metabolismo , Compuestos de Azabiciclo/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Simulación del Acoplamiento Molecular , Peptidomiméticos/síntesis química , Alineación de SecuenciaRESUMEN
Polymers prepared by chemical vapor deposition (CVD) polymerization have found broad acceptance in research and industrial applications. However, their intrinsic lack of degradability has limited wider applicability in many areas, such as biomedical devices or regenerative medicine. Herein, we demonstrate, for the first time, a backbone-degradable polymer directly synthesized via CVD. The CVD co-polymerization of [2.2]para-cyclophanes with cyclic ketene acetals, specifically 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), results in well-defined, hydrolytically degradable polymers, as confirmed by FTIR spectroscopy and ellipsometry. The degradation kinetics are dependent on the ratio of ketene acetals to [2.2]para-cyclophanes as well as the hydrophobicity of the films. These coatings address an unmet need in the biomedical polymer field, as they provide access to a wide range of reactive polymer coatings that combine interfacial multifunctionality with degradability.
Asunto(s)
Acetales/química , Técnicas de Química Sintética/métodos , Éteres Cíclicos/química , Etilenos/química , Cetonas/química , Piperidinas/química , Polimerizacion , Polímeros/química , Acetales/síntesis química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Ciclización , Éteres Cíclicos/síntesis química , Etilenos/síntesis química , Cetonas/síntesis química , Oxepinas/síntesis química , Oxepinas/química , Piperidinas/síntesis química , Polímeros/síntesis química , VolatilizaciónRESUMEN
The first enantioselective synthesis of the fungal metabolite (+)-O-methylasparvenone was achieved in eight steps and 22% overall yield from inexpensive 3,4,5-trimethoxybenzaldehyde dimethyl acetal. Key steps include (i) early-stage asymmetric alkynylation of an aromatic aldehyde with a propiolate, (ii) intramolecular Friedel-Crafts acylation, and (iii) site-selective cleavage of an aryl methyl ether.