ß-Peptides incorporating polyhydroxylated cyclohexane ß-amino acid: synthesis and conformational study.

We describe the synthesis of trihydroxylated cyclohexane ß-amino acids from (-)-shikimic acid, in their cis and trans configuration, and the incorporation of the trans isomer into a trans-2-aminocyclohexanecarboxylic acid peptide chain. Subsequently, the hydroxyl groups were partially or totally deprotected. The structural study of the new peptides by FTIR, CD, solution NMR and DFT calculations revealed that they all fold into a 14-helix secondary structure, similarly to the homooligomer of trans-2-aminocyclohexanecarboxylic acid. This means that the high degree of substitution of the cyclohexane ring of the new residue is compatible with the adoption of a stable helical secondary structure and opens opportunities for the design of more elaborate peptidic foldamers with oriented polar substituents at selected positions of the cycloalkane residues.

Stable D-xylose ditriflate in divergent syntheses of dihydroxy prolines, pyrrolidines, tetrahydrofuran-2-carboxylic acids, and cyclic ß-amino acids.

Double nucleophilic displacement of D-xylo-ditriflate by amines, water and alkyl cyanoacetates, respectively, gave a series of bicyclic divergent intermediates for the synthesis of a wide range of highly functionalized targets, including hydroxylated prolines, pyrrolidines, furanoic acids, and cyclopentanes.

Polyhydroxylated Cyclopentane ß-Amino Acids Derived from d-Mannose and d-Galactose: Synthesis and Protocol for Incorporation into Peptides.

A stereoselective synthesis of polyhydroxylated cyclopentane ß-amino acids from hexoses is reported. The reaction sequence comprises, as key steps, ring-closing metathesis of a polysubstituted diene intermediate followed by the stereoselective aza-Michael functionalization of the resulting cyclopent-1-ene-1-carboxylic acid ester. Examples of synthesis of polysubstituted 2-aminocyclopentanecarboxylic acid derivatives starting from protected d-mannose and d-galactose are presented. A general protocol for the incorporation of these highly functionalized alicyclic ß-amino acids into peptides is also reported.

New Morphiceptin Peptidomimetic Incorporating (1S,2R,3S,4S,5R)-2-Amino-3,4,5-trihydroxycyclopen-tane-1-carboxylic acid: Synthesis and Structural Study.

We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3S,4S,5R)-2-amino-3,4,5-trihydroxycyclopentane-1-carboxylic acid, previously obtained from L-idose. An optimized synthesis of this trihydroxylated cispentacin derivative is also reported. Molecular docking calculations on the target receptor support a favorable role of the hydroxy substituents of the non-natural ß-amino acid incorporated into the peptidomimetic.

Chain-Branched Polyhydroxylated Octahydro-1H-Indoles as Potential Leads against Lysosomal Storage Diseases.

Here, the synthesis and glycosidase inhibition properties of the two first known 3-ethyloctahydro-1H-indole-4,5,6-triols are reported. This study shows the transformation of d-glucose into polyhydroxylated 1-(2-nitrocyclohexane) acetaldehydes, followed by a protocol involving the formation of the azacyclopentane ring. Results of inhibitory potency assays and docking calculations show that at least one of them could be a lead for optimization in the search for compounds that behave like folding chaperones in lysosomal storage diseases.

Environmental Effects Determine the Structure of Potential ß-Amino Acid Based Foldamers.

This work shows that hybrid peptides formed by alternating trans-2-aminocyclopentanecarboxylic acid (trans-ACPC) and trans-2-aminocyclohexanecarboxylic acid (trans-ACHC) do not fold in the solvents typically used in the study of their homo-oligomers. Only when the peptides are assayed in SDS micelles are the predicted helical structures obtained. This indicates that the environment could play an equally important role (as the backbone stereochemistry) in determining their fold, possibly by providing a sequestered environment.

Protocol for the Incorporation of γ-Amino Acids into Peptides: Application to (-)-Shikimic Acid Based 2-Amino-Methylcyclohexanecarboxylic Acids.

The first example of a new protocol for the incorporation of γ-amino acids into peptides is reported. It involved a shikimic acid based stereoselective synthesis polyhydroxylated-2-nitromethylcyclohexanecarboxylic acids, which were directly incorporated into peptides.

Triacetonide of Glucoheptonic Acid in the Scalable Syntheses of d-Gulose, 6-Deoxy-d-gulose, l-Glucose, 6-Deoxy-l-glucose, and Related Sugars.

Ease of separation of petrol-soluble acetonides derived from the triacetonide of methyl glucoheptonate allows scalable syntheses of rare sugars containing the l-gluco or d-gulo structural motif with any oxidation level at the C6 or C1 position of the hexose, usually without chromatography: meso-d-glycero-d-guloheptitol available in two steps is an ideal entry point for the study of the biotechnological production of heptoses.

6-Deoxyhexoses from l-Rhamnose in the Search for Inducers of the Rhamnose Operon: Synergy of Chemistry and Biotechnology.

In the search for alternative non-metabolizable inducers in the l-rhamnose promoter system, the synthesis of fifteen 6-deoxyhexoses from l-rhamnose demonstrates the value of synergy between biotechnology and chemistry. The readily available 2,3-acetonide of rhamnonolactone allows inversion of configuration at C4 and/or C5 of rhamnose to give 6-deoxy-d-allose, 6-deoxy-d-gulose and 6-deoxy-l-talose. Highly crystalline 3,5-benzylidene rhamnonolactone gives easy access to l-quinovose (6-deoxy-l-glucose), l-olivose and rhamnose analogue with C2 azido, amino and acetamido substituents. Electrophilic fluorination of rhamnal gives a mixture of 2-deoxy-2-fluoro-l-rhamnose and 2-deoxy-2-fluoro-l-quinovose. Biotechnology provides access to 6-deoxy-l-altrose and 1-deoxy-l-fructose.

Synthetic Chemical Inducers and Genetic Decoupling Enable Orthogonal Control of the rhaBAD Promoter.

External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly used inducible expression systems, but is marred by transient expression caused by degradation of the native inducer, l-rhamnose. To address this problem, 35 analogues of l-rhamnose were screened for induction of the rhaBAD promoter, but no strong inducers were identified. In the native configuration, an inducer must bind and activate two transcriptional activators, RhaR and RhaS. Therefore, the expression system was reconfigured to decouple the rhaBAD promoter from the native rhaSR regulatory cascade so that candidate inducers need only activate the terminal transcription factor RhaS. Rescreening the 35 compounds using the modified rhaBAD expression system revealed several promising inducers. These were characterized further to determine the strength, kinetics, and concentration-dependence of induction; whether the inducer was used as a carbon source by E. coli; and the modality (distribution) of induction among populations of cells. l-Mannose was found to be the most useful orthogonal inducer, providing an even greater range of induction than the native inducer l-rhamnose, and crucially, allowing sustained induction instead of transient induction. These findings address the key limitation of the rhaBAD expression system and suggest it may now be the most suitable system for many applications.

2-Phenylaminonaphthoquinones and related compounds: synthesis, trypanocidal and cytotoxic activities.

A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds.

[Musical hallucinations: perpetual music]. / Alucinaciones musicales: la musica perpetua.

INTRODUCTION: Musical hallucinations are a kind of auditory hallucination that are prevalent among the non-psychiatric population, but which have rarely been reported in the neurological literature. They occur most frequently in the elderly, in females and when there is a loss of hearing, but their pathophysiology has still to be unravelled. CASE REPORTS: We report here six cases (five females and one male) of musical hallucinations diagnosed in a general neurology clinic over a time-span of five years. In five cases there was also concurrent hypoacusis, to a greater or lesser extent, and one had been triggered by pentoxifylline. In most instances, the musical content of the hallucinations had its origins in music experienced in childhood and early youth. In the cases submitted to pharmacological treatment, the response was poor. Yet, after explaining to the patients that the condition was benign and had no connection with a psychotic pathology, the degree of acceptance of the symptoms was good. CONCLUSIONS: Musical hallucinations are a little-known pathology lying on the borderline between neurology, otorhinolaryngology and psychiatry which are often wrongly linked to mental disease. It is essential to explain to patients and relatives that these symptoms are not necessarily of a psychiatric nature, and to be aware of the potential capacity of some commonly used drugs to generate them.

TITLE: Alucinaciones musicales: la musica perpetua.Introduccion. Las alucinaciones musicales son un tipo de alucinacion auditiva prevalente en la poblacion no psiquiatrica, pero escasamente comunicada en la bibliografia neurologica. Ocurren con mayor frecuencia en la poblacion anciana, del sexo femenino y con perdida de audicion, pero su fisiopatologia esta por desentrañar. Casos clinicos. Se presentan seis casos (cinco mujeres y un hombre) de alucinaciones musicales diagnosticados en una consulta de neurologia general en un lapso de tiempo de cinco años. En cinco de ellos concurria la hipoacusia en mayor o menor grado y uno estaba desencadenado por la pentoxifilina. En su mayoria, el contenido musical de las alucinaciones provenia de experiencias musicales vividas en la infancia y juventud. En los casos sometidos a tratamiento farmacologico la respuesta fue pobre; sin embargo, una vez explicada a los pacientes la benignidad del cuadro y su desvinculacion con patologia psicotica, el grado de aceptacion del sintoma fue bueno. Conclusiones. Las alucinaciones musicales son una patologia fronteriza entre la neurologia, la otorrinolaringologia y la psiquiatria poco conocida, que, con frecuencia, se vincula erroneamente a la enfermedad mental. Es fundamental explicar a pacientes y familiares el caracter no necesariamente psiquiatrico de este sintoma, asi como conocer la potencialidad que tienen algunos farmacos de uso comun para generarlo.

A short overview on the medicinal chemistry of (-)-shikimic acid.

Shikimic acid, a natural compound is a key intermediate in the biosynthesis of amino acids. Consequently, this derivative is widely present in many plants and has interesting biological properties. But besides the pharmacological relevance of shikimic acid itself, it is also an intermediate in the synthesis of many drugs, being the most relevant the antiviral agent oseltamivir (Tamiflu™). Here we present a short overview on recent natural, biotechnological and synthetical sources of shikimic acid, togheter with pharmacological applications of this compound and a selection of derivatives, including oseltamivir (Tamiflu™).

Síndrome de Otelo inducido por pramipexol / No disponible

No disponible

Protective effect against oxygen reactive species and skin fibroblast stimulation of Couroupita guianensis leaf extracts.

In this study, hydroalcoholic leaf extracts of Couroupita guianensis were examined for antioxidant activity, phytochemical and total phenolic composition, stimulation of human skin fibroblast (HSF) proliferation and UV-absorption. The radical scavenging capacity, reducing power and protection against joint oxidation of linoleic acid and ß-carotene bleaching oxidation in emulsion were used to evaluate the antioxidant activity. The results of this study strongly indicate in vitro antioxidant activity, which may be due to the presence of a high total phenolic content. In order to identify active principles, the extracts were submitted to fractionation and the compounds isolated were the flavonoids 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (1), 7-hydroxy-5-methoxy-6,8-dimethylflavanone (2) and the phenolic acid 4-hydroxybenzoic acid (3). In addition, a high level of stimulation of HSF proliferation and significant absorption of UV radiation were also observed. The results suggest that the hydroalcoholic leaf extracts of C. guianensis have promising skin care properties.

On a possible neutral charge state for the catalytic dyad in ß-secretase when bound to hydroxyethylene transition state analogue inhibitors.

ß-Secretase is one of the aspartic proteases involved in the formation of amyloid plaques in Alzheimer's disease patients. Our previous results using a combination of surface plasmon resonance experiments with molecular modeling calculations suggested that the Asp dyad in ß-secretase bound to hydroxylethylene containing inhibitors adopts a neutral charged state. In this work, we show that the Asp dyad diprotonated state reproduced the binding ranking of a set of these inhibitors better than alternative protonation states.

Searching the conformational space of cyclic beta-amino acid peptides.

There is an increasing interest in the secondary structure of beta-amino-acid-containing peptides, since these compounds exhibit an intrinsic propensity to form stable folds even for short peptides, a feature that is rarely observed in alpha-amino-acid-containing peptides. In this work, we use a multiple trajectory molecular dynamics approach to study a panel of cyclic beta-amino-acid-containing peptides with a variety of motifs that differ in the ring size, ring substituents, and terminal protecting groups. We find a reasonable agreement between the predicted and the experimentally observed structures, in spite of the simple solvent representation used, indicating that in most cases the folding proceeds energetically downhill and it is driven to a great extent by structural preferences coded in the internal degrees of freedom, a result supported by our energy partition analysis. Our results also show that when the N-terminal end is unprotected, it is likely to be charged in a protic polar solvent. In that case, we find that only a molecular dynamics simulation with an "all atom" solvent representation is capable of reproducing the experimentally observed secondary structure of the peptide. Finally, the time evolution analysis of the hydrogen-bond-induced turns as well as of the root-mean-square deviation from the observed structure indicates that some peptides could have a higher intrinsic flexibility than others, within a given fold, a result that correlates to some degree with our molecular mechanics energy analysis.

3-O-Benzyl-6-O-benzoyl-1,2-O-isopropil-idene-5-C-nitro-methyl-a-d-glucofuran-ose.

The title compound, C(24)H(27)NO(9), is one of the epimers of the Henry reaction of 3-O-benzyl-6-O-benzoyl-2-O-isopropyl-idene-a-d-glucofuran-5-one with nitro-methane. The conformation of the five membered rings is as expected from the precursor compound and the mol-ecule is folded with a dihedral angle of 51.4 (2)° between the aromatic rings. One O-H⋯O hydrogen bond and some intra-molecular and inter-molecular C-H⋯O inter-actions are observed in the structure.

7-hydroxy-5-methoxy-6,8-dimethylflavanone: a natural flavonoid.

The title flavonoid [systematic name: (2S)-7-hydroxy-5-methoxy-6,8-dimethyl-2-phenyl-3,4-dihydrochromen-4(2H)-one], C18H18O4, displays statistical conformational disorder, with three conformations of the molecule involving three orientations of the phenyl ring and two orientations of the fused heterocyclic ring. The conformational disorder is correlated with the isomerization equilibrium between the flavanone and chalcone forms. The conformational behaviour has a potential impact on the biological activity of this class of compounds. Moreover, pi stacking interactions at van der Waals distances are present between the aromatic rings of chroman-4-one groups of symmetry-related molecules. Apart from these pi-pi interactions, molecules are linked by strong O-H...O hydrogen bonds between hydroxy and carbonyl groups.

Ethyl 1-O-tert-butyl-dimethyl-silyl-2,3-O-isopropyl-idene-5-[(2'S)-tetra-hydro-pyran-2-yl-oxy]-d-glycero-α-d-manno-hepto-furonate.

The title compound {systematic name: (2S,3R)-ethyl 3-[(3aS,4R,6S,6aS)-6-tert-butyl-dimethyl-silyl-oxy-2,2-dimethyl-per-hydro-furo[3,4-d][1,3]dioxol-4-yl]-2-nitro-3-[(S)-tetra-hydro-2H-pyran-2-yl-oxy]propanoate}, C(23)H(41)NO(10)Si, is the product of the Henry reaction of 1-O-tert-butyl-dimethyl-silyl-2,3-O-isopropyl-idene-α-d-lyxo-penta-dialdo-1,4-furan-ose with ethyl nitro-acetate and the subsequent protection of its C-5 hydr-oxy group as tetra-hydro-pyranyl, in order to avoid the retro-Henry reaction. The tetra-hydro-pyranyl group adopts a chair conformation. The absolute configuration, assumed from the synthesis, was confirmed from the diffraction data.