S-Adenosylmethionine May Mitigate Obstructive Sleep Apnea in an Adult with Down Syndrome: A Case Report.

Obstructive sleep apnea (OSA) is common in individuals with Down syndrome (DS). These patients are characterized by reduced levels of S-adenosylmethionine (SAMe) due to a depression of mitochondrial methylation capacity, and its implementation may improve cognitive performance. Based on the above, it is likely a beneficial effect in the treatment with SAMe also on the quality of the sleep. We report the case of an adult male with DS who received benefit of SAMe administration during OSA treatment with CPAP. We observed a significant improvement of apnea/hypopnea index (AHI), which has never been previously reported in Down individuals. AHI dropped from 51.2 to 17.2 from 0 to 49 months.

Enantiomers of naringenin as pleiotropic, stereoselective inhibitors of cytochrome P450 isoforms.

Interactions between naringenin and the cytochrome P450 (CYP) system have been of interest since the first demonstration that grapefruit juice reduced CYP3A activity. The effects of naringenin on other CYP isoforms have been less investigated. In addition, it is well known that interactions with enzymes are often stereospecific, but due to the lack of readily available pure naringenin enantiomers, the enantioselectivity of its effects has not been characterized. We isolated pure naringenin enantiomers by chiral high-performance liquid chromatography and tested the ability of (R)-,(S)- and rac-naringenin to inhibit several important drug-metabolizing CYP isoforms using recombinant enzymes and pooled human liver microsomes. Naringenin was able to inhibit CYP19, CYP2C9, and CYP2C19 with IC50 values below 5 µM. No appreciable inhibition of CYP2B6 or CYP2D6 was observed at concentrations up to 10 µM. Whereas (S)-naringenin was 2-fold more potent as an inhibitor of CYP19 and CYP2C19 than (R)-naringenin, (R)-naringenin was 2-fold more potent for CYP2C9 and CYP3A. Chiral flavanones like naringenin are difficult to separate into their enantiomeric forms, but enantioselective effects may be observed that ultimately impact clinical effects. Inhibition of specific drug metabolizing enzymes by naringenin observed in vitro may be exploited to understand pharmacokinetic changes seen in vivo.

Direct high-performance liquid chromatographic separation of the enantiomers of venlafaxine and 11 analogs using amylose-derived chiral stationary phases.

A direct liquid chromatographic enantioselective separation of venlafaxine and 11 analogs was obtained in the normal phase mode using Chiralpak AD. For some compounds, a comparison between the enantioseparation using coated and immobilized amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phases (Chiralpak AD and Chiralpak IA, respectively) was made. The best separations were achieved on Chiralpak AD with ethanol as alcoholic modifier in a mobile phase made basic by DEA addition: separation factor ranges between 2.08 and 1.15 and resolution factor between 7.0 and 1.0. Using the same CSP and 2-propanol doped with TFA as acidic modifier, 10 compounds were enantioseparated with separation factor ranging between 1.40 and 1.04 and resolution factor between 3.1 and 0.3. The use of ethanol as alcoholic modifier also has the advantage of better solubility of the compounds in the mobile phase. The nature of the substituent (electron donating or withdrawing) affects in general the separation factor. A memory effect that involves a long equilibration time of the CSP is present when switching from an acidic mobile phase to a basic one.

Assessment of configurational and conformational properties of naringenin by vibrational circular dichroism.

The electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of both enantiomers of naringenin (4',5,7-trihydroxyflavanone) in acetonitrile solution have been measured. The enantiomers were obtained by chiral HPLC separation of the racemic sample. DFT calculations have been performed for relevant conformers and subsequent evaluations of VCD spectra are compared with VCD experiments: safe assignment of the absolute configuration is provided, based in particular on the VCD data. The relevance of the rotational conformers of the hydroxyl groups and of the mobility of phenol moiety is studied: based on this, we provide a first interpretation of the observed intense and broad couplet at 1325/1350 cm(-1). Four conformers contribute to this pattern with different sign and amplitude as shown by DFT calculations. Time dependent DFT calculations have been performed and compared with ECD experimental data, under the same assumption of conformational properties and mobilities investigated by VCD.

Racemization at C-2 of naringin in sour oranges with increasing maturity determined by chiral high-performance liquid chromatography.

Naringin is the major flavanone-7-O-glycoside of sour orange, and it is mainly responsible for the bitter taste of the fruit. The relative content of (2S)- and (2R)-naringin in the albedo of sour oranges during maturation in the entire season was determined by normal phase HPLC using Chiralcel OD-H as chiral stationary phase and n-hexane/ethanol doped with 0.5% of TFA as mobile phase. HPLC traces were complicated by the presence of (2S)-neohesperidin, and a software-guided analysis was developed to assess the relative amount of the C-2 diastereomers of naringin. A sigmoid curve was obtained showing variation from 94% of (2S)-naringin in very immature fruits to 69.7% in mature fruit samples. Spontaneous epimerization of (2S)-naringin in the ethanolic solutions of the albedo was noted after prolonged keeping for less acid samples. The separation of the C-2 diastereomers of other flavanoid-7-O-glycosides present in Citrus (neoeriocitrin, neohesperidin, and eriocitrin) was also obtained by chiral HPLC and afforded the identification, including stereochemistry, of the eluting peaks in the HPLC traces of the albedo extracts.

Synthesis, chiral resolution, and enantiopharmacology of a potent 2,3-benzodiazepine derivative as noncompetitive AMPA receptor antagonist.

This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (+/-)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca(2+)](i) in a primary culture of rat cerebellar granule cells which express alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (+/-)-5 at the AMPA and N-methyl-d-aspartic acid (NMDA) receptors was also evaluated.

Chiral high-performance liquid chromatographic separation and circular dichroism spectra of the enantiomers of cytotoxic aristocularine alkaloids.

The HPLC enantiomeric separation of the racemic cularinoid alkaloids N-p-methoxy-1,alpha-dihydroaristoyagonine (1) and 4',5'-demethoxy-1,alpha-dihydroaristoyagonine (2) was accomplished using five chiral stationary phases (CSPs), some of them polysaccharide-derived ones. The molecular size and conjugative effect strongly affect the different enantioselectivity of the compounds 1 and 2 on the various CSPs investigated. Single enantiomers of 1 were isolated by repeated injections on an analytical HPLC column, and their circular dichroism spectra and optical rotations were measured. The cytotoxicity of the isolated enantiomers was measured on a human colon carcinoma cell line and compared with that of the racemic compound.

Plant polyphenols as natural drugs for the management of Down syndrome and related disorders.

Polyphenols are secondary metabolites of plants largely found in fruits, vegetables, cereals and beverages, and therefore represent important constituents of the human diet. Increasing studies have demonstrated the potential beneficial effects of polyphenols on human health. Extensive reviews have discussed the protective effects of polyphenols against a series of diseases such as cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders. Limited studies have investigated the potential therapeutic effects of these natural compounds on neurodevelopmental disorders associated with intellectual disability, such as Down syndrome (DS), for which mitochondrial dysfunctions and oxidative stress are hallmarks and contribute to the deleterious symptoms and cognitive decline. This review, starting from the structure, source, bioavailability and pharmacokinetics of relevant polyphenols, highlights recent studies on the effect and potential molecular mechanism(s) of action of the phenolic compounds epigallocatechin-3-gallate, resveratrol and hydroxytyrosol in restoring mitochondrial energy deficit and in reversing phenotypical alteration in DS. The clinical implications of plant polyphenol dietary supplements as therapeutic tools in managing DS and other intellectual disability-related diseases, is also discussed.

High-performance liquid chromatographic separation and chiroptical properties of the enantiomers of naringenin and other flavanones.

The HPLC enantiomeric separation of naringenin, eriodictyol, hesperetin and pinocembrin was accomplished in the normal-phase mode using two polysaccharide-derived chiral stationary phases (Chiralcel OD-H and Chiralpak AS-H) and various n-hexane/alcohol mobile phases. The 3',4' substituents pattern affect the enantioselectivity of these phases. Single enantiomers of naringenin were isolated by semipreparative HPLC and their CD spectra were measured and related to the absolute configuration by the exciton-coupling method. Online coupling HPLC/spectropolarimeter afforded the CD sign of the eluted peaks at a single wavelength, and the complete CD spectra of the eluted enantiomers were obtained by trapping them in the spectropolarimeter cell through a switching valve.

Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones.

Oxadiazolo[3,4-c][1,4]thiazin-3-ones are cardiovascular agents that block L-type calcium channels. Previous data of cardiac and vasorelaxant activity on guinea-pig for several derivatives indicated the two positions ortho to the thiazine's sulphur as crucial for modulating the activity; but these positions are likely susceptible to metabolic biotransformations, as indicated by in silico predictions. We designed new derivatives, and obtained three negative inotropic agents with EC50 in the low nanomolar range, more potent than all the precursors published so far. In particular, benzocondensation at the thiazine ring led to 3a (EC50 = 0.013 µM) and 3b (EC50 = 0.006 µM). Besides negative inotropy, we also observed relaxant activity on nonvascular muscle in the micromolar range. We resolved the new derivatives by chiral chromatography, and determined their absolute configuration by comparing experimental and calculated chiroptical properties (VCD, ECD and ORD): they hold the same absolute configuration-optical rotation relationship, (S)-(+)/(R)-(-). Both cardiac and nonvascular activity are majorly or mostly retained in the R-form for all the compounds, but for the nonvascular activity we observed a strong stereoselectivity for 3a, with the R-form in the nanomolar range (IC50 = 0.020 µM) and 259-fold more potent than the S-one.

Synthesis, Optical Resolution and Complexation Properties of Inherently Chiral Monoalkylated p-tert-Butyl-(1,2)-calix[4]crown Ethers.

Reaction of mono-O-alkylated calix[4]arenes 2 with tri- to pentaethylene glycol ditosylates and K(2)CO(3) affords asymmetrical (1,2)-calix[4]crown ether derivatives 3 as the main product, along with minor amounts of calix[4]arene dimers 4 and mixed syn-distal di-O-alkylated calix[4]arenes 5. A reaction mechanism for the formation of 3-5 is proposed, and the NMR spectral features of these products are briefly discussed. Evidence of the chirality of 3 was provided by diastereomeric interaction with enantiopure alkylammonium salts. The enantiomeric resolution of racemates 3 was achieved by direct HPLC separation, using chiral stationary phases. A screening of the complexing abilities of pyridino-(1,2)-calix[4]crown ethers 3a-c by extraction studies from water into CH(2)Cl(2) showed a low extraction level of alkali, alkaline earth, and heavy metal picrates, while up to 25% extraction was found for Ag(+). UV and pH-metric measurements of 3a-c with silver picrate in THF indicate the formation of 1:1:1 (metal:ligand:picrate) species, with log K's in the range 3.1-3.7.

Chiral liquid chromatography separation and chiroptical properties of the enantiomers of dimethyl alpha-hydroxyfarnesylphosphonate, a precursor of a farnesyl protein transferase inhibitor.

The HPLC enantiomeric separation of racemic and non-racemic samples of dimethyl alpha-hydroxyfarnesylphosphonate (1) was accomplished using Chiralcel OD as chiral stationary phase. Single enantiomers were isolated by semipreparative HPLC and their CD spectra and optical rotations were measured. The method ascertains enantiomeric excess of 1, obtained by oxidation of dimethylfarnesylphosphonate with enantiopure oxaziridines, avoiding converting the enantiomers to diastereomers by the use of a chiral auxiliary. Stability of the solutions of 1 is strongly dependent on the nature of the solvent.

Racemization at C-2 of naringin in pummelo (Citrus grandis) with increasing maturity determined by chiral high-performance liquid chromatography.

The relative content of (2S)- and (2R)-naringin in the albedo of pummelo during maturation in the entire season was determined by normal-phase HPLC using Chiralpak IB, a polysaccharide-derived chiral stationary phase, and n-hexane/ethanol doped with 0.5% TFA as mobile phase. A sigmoid curve was obtained showing variation from 95.3% of (2S)-naringin in very immature fruits to 53% in mature fruit samples (2.3 and 14.4cm diameter, respectively). A comparison was made with previous results obtained for grapefruit and sour orange and a tentative explanation of the bitter taste of sour orange is proposed. The Chiralpak IB is much more efficient with respect to the Chiralcel OD used for the other two Citrus species and separation and resolution factors of 1.73 and 9.2, respectively, were achieved. Authentic samples of naringin and neohesperidin were also separated into their C-2 diastereomers with Chiralpak IB and isolation of the pure diastereomers of naringin was accomplished.

Resolution of phthalans obtained by ortho-litiathion of aryloxiranes by enantioselective high-performance liquid chromatography: performances of various chiral stationary phases.

The HPLC separation of the enantiomers of six phthalans (1,3-dihydrobenzo[c]furans) synthesized as racemic mixtures from ortho-lithiated aryloxiranes was accomplished in the normal-phase mode using seven polysaccharide-derived and Pirkle-type chiral stationary phases (CSPs) and n-hexane/2-propanol mixtures as mobile phases. Separation and resolution factors up to 1.6 and 4.2, respectively, were obtained. The performances of various CSPs with regard to the same compound were, however, quite different not only between the two types of CSPs but also within the same type (polysaccharide-derived or Pirkle-type). Also diastereomeric pairs of phthalans show different enantioseparation using the same CSP.

Direct high-performance liquid chromatographic separation of the enantiomers of an aromatic amine and four aminoalcohols using polysaccharide chiral stationary phases and acidic additive.

The HPLC enantiomeric separation of N-benzyl-alpha-methyl-benzylamine, phenylalaninol, tryptophanol, 2 (diphenylhydroxymethyl)pyrrolidine, and isoproterenol was accomplished in the normal-phase mode using two polysaccharide-derived chiral stationary phases (CSPs) and various n-hexane/2-propanol mobile phases with acidic (TFA) or basic (DEA) additive. The compounds were separated without any derivatization and separation factor range between 2.09 and 1.09 with resolution factor 3.4 and 0.4, respectively. The best separation of the enantiomers of the amine was achieved on amylose tris (3, 5-dimethylphenylcarbamate) CSP with TFA additive in the mobile phase; in acidic conditions, instead, the best enantioseparation of the aminoalcohols was achieved on cellulose tris (3, 5-dimethylphenilcarbamate). A long equilibration time of the CSP when switching from an undoped mobile phase to a doped one is required to obtain reproducible results.

Chiral HPLC separation and CD spectra of the C-2 diastereomers of naringin in grapefruit during maturation.

Naringin is the chief flavanone glycoside of grapefruit (Citrus paradisi). It is responsible for part of the bitter taste of the fruit and can cause the inhibition of some cytochrome P450s. The direct separation of (2R)- and (2S)-naringin in the albedo of grapefruits was obtained in normal phase HPLC mode using Chiralcel OD as chiral stationary phase and n-hexane/ethanol with 0.1% of TFA as mobile phase. Chiralpak AD was almost ineffective in the separation. This procedure was used to evaluate the stereochemistry at C-2 during maturation of the grapefruit. The CD curves of (2R)- and (2S)-naringin isolated by semipreparative chiral HPLC were determined and the elution order of the chromatographic peaks was related to the absolute C-2 configuration. Partial resolution of the C-2 diastereomers of narirutin was obtained on Chiralpak AD.

Non-empirical assignment of the absolute configuration of (-)-naringenin, by coupling the exciton analysis of the circular dichroism spectrum and the ab initio calculation of the optical rotatory power.

The non-empirical assignment of the absolute configuration of (-)-naringenin, the aglycone of (-)-naringin, a flavanone glycoside abundant in the albedo of immature grapefruits and showing several interesting biological properties, has been approached by two different methods: (a) the exciton analysis of the circular dichroism (CD) spectrum and (b) the ab initio calculation of the optical rotatory power. Both the methods indicate the configurational correlation (-)/(S), as empirically suggested by Gaffield. A comparison of advantages and limitations of the two methods of analysis is also presented.