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Vinyl-substituted carbohydrates have been synthesized from glycals derived from hexoses and pentoses. Key step is the radical reaction of xanthates in the presence of triethylborane, a non-toxic reagent. The mechanism has been investigated by isolation of various side products, which speak for a reversibility of the cyclopropylmethyl radical ring-opening. Compared to reactions with tributyltin hydride, higher regioselectivities in favor of the 2-vinyl-substituted sugars have been obtained. Yields are slightly lower with triethylborane, but all products have been isolated in analytically pure form. The new reaction is applicable to benzyl- and silyl-protected carbohydrates, which makes free sugars accessible as well. Overall, more than 15 1,2-dideoxy-2-vinyl carbohydrates have been synthesized from simple precursors in only few steps.
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We present the design of an anthracenylâ¯naphthyl (ANTâ¯NAPH) dyad and its application as a luminescent 4-stage photo switch. Both segments can individually react with singlet oxygen to switch off an optical response. In their initial form the larger ANT component reacts significantly faster and thus an ANTO2â¯NAPH stage is turned on, observed by optical response of the remaining NAPH. To reduce its reactivity, ANT is substituted with two pyridine rings. This concept is first investigated and quantified on ANT and NAPH as separated molecules. Upon protonation the reaction of ANT becomes significantly slower. For the three possible pyridyl isomers this effect increases along the order meta
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Birch reductions are well-known transformations of arenes, applied for large scale synthesis of 1,4-cyclohexadienes. Herein, we describe first reactions of benzoic acids in the presence of carbonyl compounds, affording aldol products in moderate to high yields. Alkyl aldehydes give the expected nonconjugated dienes by reaction at the α-position. Interestingly, the intermediately formed enolate attacks aryl aldehydes and ketones from its γ-position, which can be explained by steric hindrance. This opens the door for the one-pot synthesis of 1,3-cyclohexadienes, which are not accessible by classical Birch reductions. Our method is applicable to benzoic, m- and p-toluic acid and various carbonyl compounds, and more than 25 new products were isolated in up to 93 % yield. Prochiral aryl aldehydes afford diastereomeric mixtures in ratios of about 4 : 1, but in the cyclohexadiene ring only trans isomers are formed with high selectivity. Finally, the 1,3-cyclohexadienes are suitable precursors for further transformations, which we have demonstrated in first examples. Thus, aromatization affords products of a formal meta selective Friedel-Crafts alkylation, and four new stereocenters were generated by cycloaddition of singlet oxygen with excellent selectivity.
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Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogPOW larger than 3.5 and a polar surface area smaller than 100 Å2. The most effective compounds (IC50 in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.
Assuntos
Antiprotozoários , Leishmania , Animais , Antiprotozoários/farmacologia , Relação Estrutura-Atividade , Antracenos/farmacologia , Ferro/farmacologiaRESUMO
There is an ongoing interest in 1 O2 sensitizers, whose activity is selectively controlled by their interaction with DNA. To this end, we synthesized three isomeric pyridinium alkynylanthracenes 2 o-p and a water-soluble trapping reagent for 1 O2 . In water and in the absence of DNA, these dyes show a poor efficiency to sensitize the photooxygenation of the trapping reagent as they decompose due to electron transfer processes. In contrast, in the presence of DNA 1 O2 is generated from the excited DNA-bound ligand. The interactions of 2 o-p with DNA were investigated by thermal DNA melting studies, UV/vis and fluorescence spectroscopy, and linear and circular dichroism spectroscopy. Our studies revealed an intercalative binding with an orientation of the long pyridyl-alkynyl axis parallel to the main axis of the DNA base pairs. In the presence of poly(dA : dT), all three isomers show an enhanced formation of singlet oxygen, as indicated by the reaction of the latter with the trapping reagent. With green light irradiation of isomer 2 o in poly(dA : dT), the conversion rate of the trapping reagent is enhanced by a factor >10. The formation of 1 O2 was confirmed by control experiments under anaerobic conditions, in deuterated solvents, or by addition of 1 O2 quenchers. When bound to poly(dG : dC), the opposite effect was observed only for isomers 2 o and 2 m, namely the trapping reagent reacted significantly slower. Overall, we showed that pyridinium alkynylanthracenes are very useful intercalators, that exhibit an enhanced photochemical 1 O2 generation in the DNA-bound state.
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Substâncias Intercalantes , Oxigênio Singlete , Dicroísmo Circular , DNA , Desnaturação de Ácido NucleicoRESUMO
Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.
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Carboidratos/química , Naftalenos/química , Oxigênio Singlete/química , Reação de Cicloadição , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
Singlet oxygen (1O2), as an important active reagent, has found wide applications in photodynamic therapy (PDT), synthetic chemistry, and materials science. Organic conjugated aromatics serving as hosts to capture and release singlet oxygen have been systematically investigated over the last decades. Herein, we present a [6 + 6] organoplatinum(II) metallacycle by using â¼180° dipyridylanthracene donor and â¼120° Pt(II) acceptor as the building blocks, which enables the capture and release of singlet oxygen with relatively high photooxygenation and thermolysis rate constants. The photooxygenation of the metallacycle to the corresponding endoperoxide was performed by sensitized irradiation, and the resulting endoperoxide is stable at room temperature and can be stored under ambient condition over months. Upon simple heating of the neat endoperoxide under inert atmosphere at 120 °C for 4 h, the resulting endoperoxide can be reconverted to the corresponding parent form and singlet oxygen. The photooxygenation and thermolysis products were characterized by NMR spectroscopy and electrospray ionization time-of-flight mass spectrometric analysis. Density functional theory calculations were conducted in order to reveal the frontier molecular orbital interactions and reactivity. This work provides a new material platform for singlet oxygen related promising applications.
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Compostos Organometálicos/química , Compostos de Platina/química , Oxigênio Singlete/química , Hidrocarbonetos Policíclicos Aromáticos/química , Análise Espectral/métodosRESUMO
In the search of new DNA groove binding agents a series of substituted 9,10-methylpyridiniumanthracenes have been synthesized and their interactions with DNA have been studied by UV/vis absorption, CD and fluorescence spectroscopy. A minor groove binding mode is confirmed by DNA melting studies, strong CD effects, the dependence of the binding affinity on ionic strength, and the differentiation between AT and GC base pairs. No binding occurs to GC sequences. Binding constants to calf thymus DNA (ct-DNA) and poly(dA:dT) in the range between 1 × 104 and 3 × 105 M-1 have been determined. The binding strength decreases with the size of substituents attached at the anthracene site. Variation of the substitution pattern of the charged groups shows that methyl groups in meta position cause slightly stronger binding than methyl groups in para position. In contrast, with these groups in ortho position, no binding interaction has been observed. The strongest binding is achieved with an expansion of the peripheral heterocycle from pyridine to quinoline. Molecular modeling reveals the pivotal role of the substitution pattern: Anthracenes with para and meta pyridines align along the minor grooves. On the other hand, the ortho derivative adopts no groove-alignment.
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Antracenos/química , Antracenos/farmacologia , DNA/química , Dicroísmo Circular , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Conformação de Ácido Nucleico , Espectrometria de Fluorescência , Espectrofotometria Atômica/métodosRESUMO
9,10-substituted anthracenes are known for their useful optical properties like fluorescence, which makes them frequently used probes in sensing applications. In this article, we investigate the fundamental photophysical properties of three pyridyl-substituted variants. The nitrogen atoms in the pyridinium six-membered rings are located in the ortho-, meta-, and para-positions in relation to the anthracene core. Absorption, fluorescence, and transient absorption measurements were carried out and were complemented by theoretical calculations. We monitored the photophysics of the anthracene derivatives in chloroform and water investigating the protonated as well as their nonprotonated forms. We found that the optical properties of the nonprotonated forms are strongly determined by the anthracene chromophore, with only small differences to other 9,10-substituted anthracenes, for example diphenyl anthracene. In contrast, protonation leads to a strong decrease in fluorescence intensity and lifetime. Transient absorption measurements and theoretical calculations revealed the formation of a charge-transfer state in the protonated chromophores, where electron density is shifted from the anthracene moiety toward the protonated pyridyl substituents. While the para- and ortho-derivatives' charge transfer is still moderately fluorescent, the meta-derivative is affected much stronger and shows nearly no fluorescence. This nitrogen-atom-position-dependent sensitivity to hydronium activity makes a combination of these fluorophores very attractive for pH-sensing applications covering a broadened pH range.
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Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs) have so far been only technically used and not explored for their leishmanicidal potential. This study verified the in vitro efficiency and mechanism of AcEPs against both Leishmania promastigotes and axenic amastigotes (L. tarentolae and L. donovani) as well as their toxicity in J774 macrophages. Additionally, the kinetics and radical products of AcEPs' reaction with iron, the formation of radicals by AcEPs in Leishmania, as well as the resulting impairment of parasite mitochondrial functions were studied. Using electron paramagnetic resonance combined with spin trapping, photometry, and fluorescence-based oximetry, AcEPs were demonstrated to (i) show antileishmanial activity in vitro at IC50 values in a low micromolar range, (ii) exhibit host cell toxicity in J774 macrophages, (iii) react rapidly with iron (II) resulting in the formation of oxygen- and carbon-centered radicals, (iv) produce carbon-centered radicals which could secondarily trigger superoxide radical formation in Leishmania, and (v) impair mitochondrial functions in Leishmania during parasite killing. Overall, the data of different AcEPs demonstrate that their structures besides the peroxo bridge strongly influence their activity and mechanism of their antileishmanial action.
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Antracenos/metabolismo , Leishmania/metabolismo , Mitocôndrias/metabolismo , Peróxidos/metabolismo , Animais , Antracenos/química , Linhagem Celular , Sobrevivência Celular , Espectroscopia de Ressonância de Spin Eletrônica , Concentração Inibidora 50 , Ferro/farmacologia , Leishmania/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos , Peróxidos/química , Superóxidos/metabolismoRESUMO
The generation of reactive singlet oxygen under mild conditions is of current interest in chemistry, biology, and medicine. We were able to release oxygen from dipyridylanthracene endoperoxides (EPOs) by using a simple chemical trigger at low temperature. Protonation and methylation of such EPOs strongly accelerated these reactions. Furthermore, the methyl pyridinium derivatives are water soluble and therefore serve as oxygen carriers in aqueous media. Methylation of the EPO of the ortho isomer affords the parent form directly without increasing the temperature under very mild conditions. This exceptional behavior is ascribed to the close contact between the nitrogen atom and the peroxo group. Singlet oxygen is released upon this reaction, and can be used to oxygenate an acceptor such as tetramethylethylene in the dark with no heating. Thus, a new chemical source of singlet oxygen has been found, which is triggered by a simple stimulus.
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Carbohydrates carrying thiol groups at the C-2 position have been attached to gold nanoparticles (AuNPs) with stereocenters in close proximity to the surface for the first time. Their configurations can be clearly distinguished by the tendency of particle aggregation. AuNP surface plasmon resonance (SPR), X-ray photoelectron spectroscopy (XPS), and IR spectroscopy indicate that the thiocarbohydrates replace citrate molecules at different rates, causing aggregation and eventually precipitation. A quantitative formulation of this aggregation process shows that reactivities can vary by several magnitudes. Adsorption isotherms and kinetics also demonstrate that the number of thiocarbohydrates varies by a factor of two. Molecular mechanics force field (MMFF) calculations reveal their relative orientations. Based on these models, the different binding behavior can be ascribed to attractive van der Waals forces and hydrogen bonds. Such interactions occur either between the carbohydrate and AuNPs, by lateral intermolecular forces at the surface, or by interparticle attraction, in analogy to cell-surface carbohydrates of biological recognition systems. Aggregation of NPs therefore act as an indicator to differentiate between various carbohydrates with defined configurations.
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The ortho, meta, and para isomers of 9,10-dipyridylanthracene 1 have been synthesized and converted into their endoperoxides 1-O2 upon oxidation with singlet oxygen. The kinetics of this reaction can be controlled by the substitution pattern and the solvent: in highly polar solvents, the meta isomer is the most reactive, whereas the ortho isomer is oxidized fastest in nonpolar solvents. Heating of the endoperoxides affords the parent anthracenes by release of singlet oxygen.
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The conformational equilibrium of the axial/equatorial conformers of 4-methylene-cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon mixture. At 153 K, the ring interconversion gets slow on the nuclear magnetic resonance timescale, the conformational equilibrium (-ΔG°) can be examined, and the barrier to ring interconversion (ΔG# ) can be determined. The structural influence of sp2 hybridization on both ΔG° and ΔG# of the cyclohexyl moiety can be quantified.
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Herein, we present a model system that allows the investigation of a directed intramolecular singlet oxygen ((1)O2) transfer. Furthermore, we show the influence of singlet oxygen lifetime and diffusion coefficient (D) on the preference of the intramolecular reaction over the intermolecular one in competition experiments. Finally, we demonstrate the distance dependence in quenching experiments, which enables us to draw conclusions about the role of singlet oxygen and (1)O2 carriers in photodynamic therapy.
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A convenient and general synthesis of 2-thiocarbohydrates via cerium ammonium nitrate oxidation of the thiocyanate ion is described. Radical addition to glycals proceeds with excellent regio- and good stereoselectivities in only one step, deprotection affords water-soluble 2-thio saccharides. Binding studies to Con A have been performed by isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR spectroscopy. The 2-thiomannose derivative binds even stronger to Con A than the natural substrate, offering opportunities for new lectin or enzyme inhibitors.
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The intramolecular transfer of energy (FRET) and electrons (Dexter) are of great interest for the scientific community and are well-understood. In contrast, the intramolecular transfer of singlet oxygen ((1)O2), a reactive and short-lived oxygen species, has until now been unknown. This process would be very interesting because (1)O2 plays an important role in photodynamic therapy (PDT). Herein, we present the first successful intramolecular transfer of (1)O2 from a donor to acceptor. Also, we found a dependence of conformation and temperature comparable with those of FRET. We provide several pieces of evidence for the intramolecular character of this transfer, including competition experiments. Our studies should be interesting not only from the theoretical and mechanistic point of view but also for the design of new (1)O2 donors and applications in PDT.
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Conformationally fixed carbohydrate analogues are promising small-molecule inhibitors for hydrolases like O-GlcNAcase (OGA); however, their synthesis usually requires many steps. Herein we describe cycloadditions of dichloroketene to various glycals and subsequent Beckmann rearrangements, which offer an easy and stereoselective entry to glycosamine derivatives in good yields. The reactions are applicable for hexoses, pentoses, and disaccharides, and transformations to the corresponding imidates proceed smoothly. First biological tests reveal that such imidates indeed inhibit human OGA.
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Carboidratos/síntese química , Dissacarídeos/química , Glucosamina/síntese química , beta-N-Acetil-Hexosaminidases/síntese química , Fenômenos Bioquímicos , Carboidratos/química , Glucosamina/química , Conformação Molecular , Estrutura Molecular , Estereoisomerismo , beta-N-Acetil-Hexosaminidases/químicaRESUMO
Singlet oxygen donors are of current interest for medical applications, but suffer from a short half-life leading to low singlet oxygen yields and problems with storage. We have synthesized more than 25 new singlet oxygen donors based on differently substituted naphthalenes in only a few steps. The influence of functional groups on the reaction rate of the photooxygenations, thermolysis, half-life, and singlet oxygen yield has been thoroughly studied. We determined various thermodynamic data and compared them with density functional calculations. Interestingly, remarkable stabilities of functional groups during the photooxygenations and stabilizing effects for some endoperoxides during the thermolysis have been found. Furthermore, we give evidence for a partly concerted and partly stepwise thermolysis mechanism leading to singlet and triplet oxygen, respectively. Our results might be interesting for "dark oxygenations" and future applications in medicine.
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An experimental and computational study on the impact of functional groups on the oxidation stability of higher acenes is presented. We synthesized anthracenes, tetracenes, and pentacenes with various substituents at the periphery, identified their photooxygenation products, and measured the kinetics. Furthermore, the products obtained from thermolysis and the kinetics of the thermolysis are investigated. Density functional theory is applied in order to predict reaction energies, frontier molecular orbital interactions, and radical stabilization energies. The combined results allow us to describe the mechanisms of the oxidations and the subsequent thermolysis. We found that the alkynyl group not only enhances the oxidation stability of acenes but also protects the resulting endoperoxides from thermal decomposition. Additionally, such substituents increase the regioselectivity of the photooxygenation of tetracenes and pentacenes. For the first time, we oxidized alkynylpentacenes by using chemically generated singlet oxygen ((1)O(2)) without irradiation and identified a 6,13-endoperoxide as the sole regioisomer. The bimolecular rate constant of this oxidation amounts to only 1 × 10(5) s(-1) M(-1). This unexpectedly slow reaction is a result of a physical deactivation of (1)O(2). In contrast to unsubstituted or aryl-substituted acenes, photooxygenation of alkynyl-substituted acenes proceeds most likely by a concerted mechanism, while the thermolysis is well explained by the formation of radical intermediates. Our results should be important for the future design of oxidation stable acene-based semiconductors.