Butyl Derivative Research Articles

Synthetic Bilayers on Mica from Self-Assembly of Hydrogen-Bonded Triazines.

This study describes organic thin films prepared under a range of conditions from a model series of bis-N-alkyl chloro-triazines functionalized with short alkyl chains from ethyl to hexyl. The pure films were characterized using atomic force microscopy (AFM), X-ray diffraction (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). When cast on mica, these compounds assemble as crystalline sheets made up of a synthetic bilayer along the crystallographic ab-plane with an internal hydrogen-bonded domain between external alkyl chains. These micron-scale surfaces stack along the c-axis, and increasing the alkyl chain length results in changes to the crystal morphology from needles to nanoscale plates. Thicker films produce nanoscale, pyramidal stacks of bilayers. Compared to atomically flat mica, a rougher, unetched silicon substrate produced irregular domains in the secondary bilayer. Films of mixtures comprising the ethyl derivative with butyl, pentyl, or hexyl derivative were imaged using time-of-flight secondary-ion mass spectrometry (ToF-SIMS) that indicated a trend toward a constant stoichiometry with increasing alkyl chain length. AFM of mixed films on mica showed single bilayers of height <2 nm, with an acceptable correlation to the XRD measurements, supporting a constant stoichiometry. These materials permit easy modification of mica to a micron-scale, atomically flat hydrophobic surface, and the use of mixtures with different alkyl chain lengths suggests a method to improve the quality of functional organic thin films.

Potential biodiesel production from Brazilian plant oils and spent coffee grounds by Beauveria bassiana lipase 1 expressed in Aspergillus nidulans A773 using different agroindustry inputs

This paper describes the obtaining of fatty acids ethyl esters from Açaí (Euterpe oleracea Martius), Buriti (Mauritia flexuosa) and spent coffee grounds oils using a Beauveria bassiana lipase expressed in Aspergillus nidulans, which gene was cloned in pExpyr vector. Carbon sources were tested to enhance recombinant lipase secretion. Cassava peels, corn meal, corn syrup, sorghum seed and wheat bran induced higher lipase activity. Monosaccharides, when combined to previously cited carbon sources, interfered at lipase production: fructose and glucose enhanced lipase production, especially on sorghum seed and wheat bran cultures; while xylose diminished its production. Lipase was immobilized on hydrophobic resins, and derivatives were characterized using pNPP transesterification with ethanol as co-substrate. Sepabead-C18 derivative demonstrated as better pNPP transesterification catalyzer, being 2-fold higher than butyl derivative. The Sepabead-C18 derivative was biochemically characterized using different temperatures and solvents. The transesterification of Açaí, Buriti and coffee spent grounds oils were performed with cyclohexane, and the product content was quantified using gas-chromatography as 17.1%, 5.0%, and 3.4%, respectively. The results demonstrated the potential of immobilized heterologous lipases to produce ethyl ester from Brazilian natural oils and a common food waste. This work will improve the enzymatic methodologies for biodiesel industry.

COMPUTATIONAL STUDY OF BUTYL AND NAPHTHYL AMINE DERIVATIVE OF PERYLENE DIIMIDES TARGETTING TELOMERASE ENZYME FOR ANTICANCER ACTIVITY

Objective: Telomeres are protective caps present at the end of the chromosomes and it contains genetic information. From the literature survey, we selected perylene diimides which interact with the telomerase enzyme and possess anticancer activity. Telomestatin a macrocyclic chemical compound that inhibits telomerase activity as well it induces the formation of G-Quadruplex structures in the telomeric region. The main objective of the study was to find the binding affinity of butyl and naphthyl amine derivative of perylene ligands targeting telomerase enzyme for anticancer activity. Telomerase enzyme is responsible for maintaining the length of telomeres and keeping the chromosomes intact longer. Telomeres will become increasingly common with age. Perylene diimides and its derivatives show good biological activity and also in vitro studies possess efficient anticancer agent. The butyl and naphthyl amine derivatives are screened by computational techniques to study regarding binding energy and ligand interactions with respect to the targets.Methods: Butyl and naphthyl amine derivative of perylene diimides is drawn using Accelrys Draw. The structures are retrieved from the previous study. The structures are converted to pdb formats using Discovery Studio Visualizer 4.1. The study was to investigate the binding energy values of butyl and naphthyl amine derivatives of perylene diimides. Auto Dock 4.2 was used to dock the ligand with the targets. The target selected for docking was 3CE5 and 4B18. The results are visualized by Discovery Studio Visualizer 4.1. The results are compared with the standard drug N,N’-bis-(2-(1- piperidino)ethyl)-3,4,9,10-perylene tetracarboxylic acid diimide (PIPER).Results: From the results, butylamine derivative of perylene diimide possesses good binding energy when compared with standard drug PIPER. This result shows that the butylamine will be effective for anticancer therapy. In future, in vivo studies of butylamine derivative of perylene diimide will be carried out.

The influence of two imidazolium-based ionic liquids on the structure and activity of glucose oxidase: Experimental and theoretical studies

The search for ionic liquids (ILs) with biochemical and biomedical applications has recently gained great attention. IL containing solvents can change the structure, stability and function of proteins. The study of protein conformation in ILs is important to understand enzymatic activity. In this work, conformational stability and activity of the enzyme in two imidazolium-based ILs (1-butyl 3-methyl-imidozolium and 1-hexyl 3-methyl-imidozoliumbromides) were investigated. We treated glucose oxidase as dimer-active enzyme in different IL concentration and seen that GOx activity was inhibited in the presence of ILs. Our experimental data showed that inhibition of activity and reduction of enzyme tertiary structure are more for hexyl than butyl derivative. These experimental results are in agreement with foregoing observations. To find a possible mechanism, a series of molecular dynamics simulation of the enzyme were performed at different IL concentration. The structure parameters obtained from MD simulation showed that conformational changes at the active site and FAD-binding site support the hypothesis of enzyme inhibition at the presence of ILs. Root mean square deviation and fluctuation calculations indicated that the enzyme has stable conformation at higher IL concentration, in agreement with experimental observation. But hexyl derivative has a much stronger stabilization effect on the protein structure. In summary, the present study could improve our understanding of the molecular mechanism about the ionic liquid effects on the structure and activity of proteins.

Cytotoxic and Antimicrobial Activity of Dehydrozingerone based Cyclopropyl Derivatives.

A small series of 1-acetyl-2-(4-alkoxy-3-methoxyphenyl)cyclopropanes was prepared, starting from dehydrozingerone (4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one) and its O-alkyl derivatives. Their microbiological activities toward some strains of bacteria and fungi were tested, as well as their in vitro cytotoxic activity against some cancer cell lines (HeLa, LS174 and A549). All synthesized compounds showed significant antimicrobial activity and expressed cytotoxic activity against tested carcinoma cell lines, but they showed no significant influence on normal cell line (MRC5). Butyl derivative is the most active on HeLa cells (IC50 = 8.63 μm), while benzyl one is active against LS174 and A549 cell lines (IC50 = 10.17 and 12.15 μm, respectively).

Phenanthroimidazole Derivative as an Easily Accessible Emitter for Non-Doped Light-Emitting Electrochemical Cells

We report a versatile approach to harvest electroluminescence from a nondoped light-emitting electrochemical cell (LEC) using an easily accessible phenanthroimidazole derivative. The authors investigated two different types, (i) ionic and (ii) neutral phenanthroimidazole derivatives by modifying our previously reported LEC emitter. Sky-blue electroluminescence was achieved by applying these modified emitter in LEC devices. In comparison to the parent molecule, a highly contrasting performance was exhibited by all the modified emitters except the neutral butyl derivative (nbpypn). By employing an ionic molecule (ihpypn) in a fully solution-processed typical LEC device structure, a peak brightness of 711 cd/m2 was observed at a current efficiency of 0.18 cd/A. Our champion device (ihpypn-LEC) presented a 5-fold increase in maximum brightness at a ten times higher current density than its parent molecule. These peak brightness values are among the best comparing to those reported for LECs with the correspond...

Alkyl Substituent Effects on Molecular Packing and Optoelectronic Properties of 2,3-Dialkyltetracenes

Abstract A series of 2,3-dialkyltetracenes (alkyl = propyl to hexyl) were readily prepared from 2,3-dialkyl-5,12-tetracenequinone by a one-pot sequence involving hydride reduction with sodium borohydride and subsequent addition of tin(II) chloride in concd hydrochloric acid. X-ray diffraction patterns of their recrystallized powder samples demonstrated their crystalline nature. X-ray crystallographic analysis of the butyl derivative revealed that there were two disordered sets of butyl groups with 50% occupancies, and that in the molecular structure, one butyl group was coplanar with the tetracene core, while the other butyl group was perpendicular to the tetracene plane. Further, the crystal structure adopted a repeating bilayer structure of herringbone-packed tetracene cores and disordered alkyl groups. The conformational analysis demonstrated that there were a number of stable conformers, which would account for the occurrence of alkyl disorders. Flash-photolysis time-resolved microwave conductivity (FP-TRMC) measurements of 2,3-dialkyltetracenes exhibited an increase in the product of charge carrier mobility (3.0 × 10−5 to 3.5 × 10−4 cm2 V−1 s−1) and its generation efficiency with increase in the length of the alkyl side chains, suggesting that a longer alkyl side chain plays an important role in the degree of transfer integral and in the suppression of charge recombination or exciton quenching.

Gelation and Structural Transformation Study of Some 1,3,5-Benzenetricarboxamide Derivatives

Short-chain analogues of N,N′,N″-tris-(4-alkylphenyl)-1,3,5-benzenetricarboxamide derivatives (methyl to butyl) are prepared, and their gelation study renders a positive result for all, except the butyl derivative, in both DMSO and DMSO/H2O. The crystal structure analysis of the parent compound (1a) and its methyl (1b) and butyl (1e) derivatives shows columnar structures. However, a notable difference has been observed within the columnar structures of 1a or 1b and 1e. Detailed structural analysis was carried out to reason such varied molecular assemblies, based on the deviation angle of amide groups, along with the aid of some reported examples that reveal the structural transformation of 1,3,5-benzenetricarboxamide derivatives from sheets to different columnar structures. In addition, similarity in the simulated powder pattern of the DMSO adducts of 1a and 1b and the experimental powder pattern of the xerogels of 1a and 1b indicates the possibility of similar packing in both crystals and the fibers of the gel.

Isomeric and chemical consequences of the direct magnesiation of 1,3-benzoazoles using β-diketiminate-stabilized magnesium bases

Opening-up new synthetic applications of β-diketiminate stabilised magnesium complexes, this case study compares the ability of the alkyl [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(THF)] (1) and the amido reagent [{Ar*NC(Me)CHC(Me)NAr*}Mg(TMP)] (2) (Ar* = 2,6-i-Pr2-C6H3) to promote direct Mg–H exchange towards the series of 1,3-benzoazoles: benzoxazole (boz), benzothiazole (btz) and N-methyl benzimidazole (bImMe). Both reagents deprotonate boz at room temperature to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{O(o-C6H4)NC}(THF)] (3) via the C–O bond cleavage of a putative C2-magnesiated-benzoxazolyl intermediate. Structurally tracking the reactivity of 1 and 2 towards less acidic btz and bImMe showed that the behaviour of reagents 1 and 2 diverged dramatically. Kinetically activated TMP-reagent 2 effectively promotes the deprotonative magnesiation of btz and bImMe under mild reaction conditions, giving the alpha-metallated intermediates [{Ar*NC(Me)CHC(Me)NAr*}2Mg2{btz*}2] (4) and [{Ar*NC(Me)CHC(Me)NAr*}2Mg2{bImMe*}2] (7) (btz* = 2-benzothiazolyl; bImMe* = 2-N-methylbenzimidazolyl). Analysis of crystallographic and NMR data revealed that in 4 and 7 the metallated carbon atoms display a markedly carbenic character and that in solution these species exist at room temperature solely as the ring-closed products, without any observable equilibration to the acyclic isomers. Contrastingly, alkyl reagent 1 decreases the magnesiation rate of btz facilitating an intriguing new cascade activation process of two molecules of substrate involving a sequence of deprotonation/coordination/C–C coupling and ring-opening reactions to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{(btz*)C(H)N(o-C6H4)S}] (5). Hydrolysis of 5 followed by addition of the radical oxidant TEMPO ultimately produces the homocoupled product bis(benzothiazole) 6 in a 72% isolated yield. Thus, this establishes a novel transition-metal-free method to prepare homocoupled thiazoles. More straightforwardly, the coordination product [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(bImMe)] (8) was obtained when equimolar amounts of bImMe and 1 were reacted, illustrating the kinetic stubbornness of the Mg–C bond in butyl derivative 1. Complex 8 can be envisaged as a valuable guide to the constitution of a premetallation complex (in relation to the complex-induced proximity effect, CIPE).

Neuroprotective effect of alkyl hydroxytyrosyl ethers in rat brain slices subjected to a hypoxia-reoxygenation model

The aim of the present study was to investigate the antioxidant and possible neuroprotective and antioxidant effects of five alkyl hydroxytyrosyl (HT) ethers (ethyl, butyl, hexyl, octyl and dodecyl) in rat brain slices. None of the compounds modified lipid peroxidation or glutathione concentrations (GSH) in oxygenated samples. The effects of oxidative stress were investigated with ferrous salts to induce lipid peroxidation and diethylmaleate (DEM) to reduce GSH. All compounds inhibited lipid peroxidation with an inhibitory concentration 50% (IC(50)) one tenth that of HT. These compounds, especially the butyl derivative, prevented GSH depletion after incubation with DEM. We also explored the neuroprotective effect of these compounds in an experimental model of hypoxia-reoxygenation in rat brain slices. All compounds showed neuroprotective and antioxidant effects. Our results established a relationship between these effects and the length of the carbon chain (maximum effect in the range of C4-C8).

ChemInform Abstract: Transition Metal Complexes with Sulfur Ligands. Part 56. First Metal Complexes of the Crown Thioether bzo2-18S6 and Its Tertiary Butyl Derivative bubzo2-18S6 with Ru, Ag, Cr, Mo, W and Fe. X-Ray Structure Analysis of (Ru(bzo2-18S6))(P

ChemInform Abstract: Transition Metal Complexes with Sulfur Ligands. Part 56. First Metal Complexes of the Crown Thioether bzo2-18S6 and Its Tertiary Butyl Derivative bubzo2-18S6 with Ru, Ag, Cr, Mo, W and Fe. X-Ray Structure Analysis of (Ru(bzo2-18S6))(P

Dynamic thermodynamic resolution of lithiated N-Boc-N′-alkylpiperazines

Abstract Deprotonation of N -Boc- N ′-alkylpiperazines with sec -BuLi in Et 2 O–TMEDA gave the 2-lithio derivatives which were resolved in the presence of a chiral ligand. The best ligands for the asymmetric substitution were diamino-alkoxides that promoted a dynamic thermodynamic resolution (DTR) of the organolithium at −30 °C. Electrophilic quench gave enantiomerically enriched 2-substituted piperazines. Of a selection of piperazines, the N ′- t -butyl derivative gave the best results, with the product N -Boc- N ′- t -butyl-2-substituted piperazines being formed with enantiomer ratios up to 81:19.

Synthesis and Crystallochromy of 1,4,7,10‐Tetraalkyltetracenes: Tuning of Solid‐State Optical Properties of Tetracenes by Alkyl Side‐Chain Length

We synthesized a series of 1,4,7,10-tetraalkyltetracenes using a new 2,6-naphthodiyne precursor and 2,5-dialkylfurans as starting materials (alkyl=methyl to hexyl). Surprisingly, the solid-state color of the tetracenes ranges through yellow, orange, and red. Both yellow and red solids are obtained for the butyl derivative. Optical properties in solution show no marked differences; however, those in the solid state show characteristics that vary with alkyl side-chain length: methyl, propyl, and pentyl derivatives are orange; ethyl and butyl derivatives are yellow; and another butyl and hexyl derivative are red. X-ray analyses reveal that the molecular structures are planar, semi-chair, or chair forms; the chair form takes a herringbone-like arrangement and the other forms take slipped parallel arrangements. The mechanism of crystallochromy is discussed in terms of molecular structure, crystal packing, and calculations that take account of exciton coupling.

Intercalation of stable organic radicals into layered saponite clay

2-(3- and 4-N-methylpyridinium)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxyl 3-N-oxide (abbreviated as m- and p-MPYNN), the butyl derivative (m- and p-BuPYNN), 4-(N-ethylammonium)-2,2,5,5-tetramethylpiperidin-1-oxyl (ETEP) and N,N,N',N'-Tetramethyl-1,4-phenylenediamine radical cation (TMPD(+)) have been successfully intercalated into saponite clay. The amount of intercalated material has been determined via UV/VIS spectroscopy, elemental analysis and EPR spectroscopy, and the expansion of the layer distance from approximately 12.0 to ca. 15 A has been measured by X-ray powder diffraction. The magnetic properties of these materials, which result from the interplay of the modified intermolecular interactions between the guest species, and the additional interaction with the host lattice, have been characterized by magnetic susceptibility, EPR and solid state NMR measurements. While the (29)Si and (27)Al NMR spectra show little influence of the radical species on the local structural environments of the nuclei in the host lattice, the guest-host interaction manifests itself in significant line-broadening and (in some cases) resonance displacements of the (1)H NMR signals belonging to the molecular radical cations. In the case of TMPD(+) intercalates, the NMR and EPR data indicate predominant radical dimerization within the interlayer space.

Novel Ascorbic Acid Based Ionic Liquids for the In Situ Synthesis of Quasi‐Spherical and Anisotropic Gold Nanostructures in Aqueous Medium

A series of newly designed ascorbic acid based room temperature ionic liquids were successfully used to prepare quasi-spherical and anisotropic gold nanostructures in an aqueous medium at ambient temperature. The synthesis of these room temperature ionic liquids involves, first, the preparation of a 1-alkyl (such as methyl, ethyl, butyl, hexyl, octyl, and decyl) derivative of 3-methylimidazolium hydroxide followed by the neutralization of the derivatised product with ascorbic acid. These ionic liquids show significantly better thermal stability and their glass transition temperature (Tg) decreases with increasing alkyl chain length. The ascorbate counter anion of these ionic liquids acts as a reducing agent for HAuCl4 to produce metallic gold and the alkylated imidazolium counter cation acts as a capping/shape-directing agent. It has been found that the nature of the ionic liquids and the mole ratio of ionic liquid to HAuCl4 has a significant effect on the morphology of the formed gold nanostructures. If an equimolar mixture of ionic liquid and HAuCl4 is used, predominantly anisotropic gold nanostructures are formed and by varying the alkyl chain length attached to imidazolium cation of the ionic liquids, various particle morphologies can formed, such as quasispherical, raspberry-like, flakes or dendritic. A probable formation mechanism for such anisotropic gold nanostructures has been proposed, which is based on the results of some control experiments.

Synthesis, structure and cytotoxicity of diorganotin(IV) complexes of 2,6-lutidine-α 2,3-diol (Lu): The crystal structures of Lu and [SnMe 2(H 2O)(Lu-2H)

The reaction of dimethyl-, diethyl- and dibutyltin(IV) oxide with 2,6-lutidine-α 2,3-diol (Lu) [2-(hydroxymethyl)-3-hydroxy-6-methylpyridine] in toluene/ethanol has been investigated. The compounds were isolated and characterized by IR, Raman and Mössbauer spectroscopy, EI and FAB mass spectrometry and 1H and 119Sn NMR spectroscopy. The structures of Lu and [SnMe 2(H 2O)(Lu-2H)] were determined by X-ray diffraction. The crystal of [SnMe 2(H 2O)(Lu-2H)] contains dimeric [SnMe 2(H 2O)(Lu-2H)] 2 units, in which the tin atom is coordinated to the O atoms of the two deprotonated hydroxymethyl groups and one deprotonated phenolic hydroxyl group. The distorted octahedral coordination polyhedron of each tin atom is completed by a water molecule and two methyl C atoms. The butyl derivative exhibited significant in vitro antitumor activity against the human carcinoma cell lines HeLa-229, A2780 and A2780cis, although minor than that of the pyridoxine derivative prepared previously.

Immobilization of Zinc Phthalocyanines in Silicate Matrices and Investigation of Their Photobactericidal Effect on E.coli

The aim of the present investigation was to immobilize zinc phthalocyanines in a silicate matrix and to test the photobactericidal properties of the matrices so prepared toward Esherichia coli in model aqueous media. For the purpose, tetra tertiary butyl zinc phthalocyanine (TBZnPc) and zinc phthalocyanine tetrasulfonic acid (ZnPcTS) were used. The abilities of these two photosensitizers to generate singlet oxygen in solution were compared by following the rate of photobleaching of 1,3-diphenylisobenzofuran (DPBF) at 430 nm in dimethylformamide (DMF).The results of this study show clearly that, under the conditions used here, the TBZnPc is the more effective generator of singlet oxygen; with it the DPBF was virtually completely photobleached in 4 min, while with the ZnPcTS under the same conditions, it took 12 min to reach this point. Glass conjugates with the two phthalocyanines were obtained by the sol-gel technique and were characterized by a well-defined color due to the phthalocyanine incorporated in the silicate matrix. Glasses with an intense, but inhomogeneous, green color were obtained when the tetrasulfonic derivative of the zinc phthalocyanine was used, while blue glasses of evenly distributed coloration were formed from the tetra tertiary butyl derivative.The ZnPcTS conjugate demonstrates more effective singlet oxygen evolution than is the case with the TBZnPc conjugate. These results are the opposite of those obtained for the free phthalocyanines in solution. The structural formulae of the compounds show that TBZnPc has a more pronounced hydrophobic character than the sulfonic derivative. In our view, the relative reactivities of the conjugates can be explained by the tetrasulfonic derivative being situated mainly in the surface parts of the glass matrix where the hydrophilic character is prevailing, while the tertiary butyl derivative is mainly present in the internal parts of the matrix as a result of which it is less accessible and therefore less activeThe results obtained on the effect of zinc phthalocyanine conjugates on E. coli show a trend similar to that observed with singlet oxygen evolution shown. Thus, for the ZnPcTS conjugate, the log kill is 1.32 and for the TBZnPc conjugate, it is 0.98, in each case after 120 min. The results obtained show that phthalocyanines can be immobilized successfully in a silicate matrix and used for photodisinfection of microbially polluted waters. The silicate matrix has some advantages in comparison with other organic matrices. It is insoluble in water, resistant towards microorganisms, easy to fabricate, and might be developed successfully for the photodisinfection of water, e.g., in swimming pools and in other open water reservoirs.

3,3′-Diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5

3,3'-Diindolylmethane (DIM), ring-substituted DIMs and 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes (C-DIMs) inhibit growth of Panc-1 and Panc-28 pancreatic cancer cells. Although DIMs (diarylmethanes) and selected C-DIMs (triarylmethanes), such as the p-t-butyl derivative (DIM-C-pPhtBu), activate the aryl hydrocarbon receptor and peroxisome proliferator-activated receptor gamma, respectively, this study shows that both DIM and DIM-C-pPhtBu induce common receptor-independent pathways. Both DIM and DIM-C-pPhtBu increased endoplasmic reticulum (ER) staining and ER calcium release in Panc-1 cells, and this was accompanied by increased expression of glucose related protein 78 and C/EBP homologous transcription factor (CHOP/GADD153) proteins. Similar results were observed after treatment with thapsigargin (Tg), a prototypical inducer of ER stress. The subsequent downstream effects of DIM/DIM-C-pPhtBu- and Tg-induced ER stress included CHOP-dependent induction of death receptor DR5 and subsequent cleavage of caspase 8, caspase 3, Bid and PARP. Activation of both receptor-dependent and receptor-independent (ER stress) pathways by DIM and DIM-C-pPhtBu in pancreatic cancer cells enhances the efficacy and potential clinical importance of these compounds for cancer chemotherapeutic applications.

A novel, quantitative assay for homocarnosine in cerebrospinal fluid using stable-isotope dilution liquid chromatography–tandem mass spectrometry

We describe a rapid and sensitive method for the quantification of homocarnosine in physiological fluids, with particular emphasis on cerebrospinal fluid (CSF). Homocarnosine was quantified as the butyl derivative, with (2)H(2)-l-homocarnosine as internal standard. Following deproteinization of CSF samples, supernatants were evaporated to dryness and derivatized with 10% 6M HCl in butanol. Samples were chromatographed on a C(18) column and detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) operating in the multiple reaction monitoring mode. The intra- and inter-assay variations were 4.6 and 10.9%, respectively. Mean recovery of homocarnosine at two concentrations was 105%. The limit of detection in CSF approximated 20 nmol/L. CSF homocarnosine is age dependent and ranges from <0.02 to 10 micromol/L. Our method is applicable to the analysis of CSF derived from patients with heritable defects in the GABA pathway, patients with homocarnosinosis or serum carnosinase deficiency, and should be applicable to other model systems in order to further explore the biological role and significance of homocarnosine in mammalian systems.

Synthesis and In Vitro Skin Permeation of Naproxen Conjugates with &amp;#945;- Alkylamino Acids

Novel amide conjugates of the NSAID naproxen (NAP, 1) with short-chain alpha-alkylamino acids (C4 to C6 alkyl chain) were synthesized through a carbodiimide (EDAC)-assisted coupling reaction and evaluated as dermal prodrugs of NAP. The 2-alpha-aminobutyl derivative (2) showed lipophilicity similar to that of NAP, while the higher homologues (3) and (4) were more lipophilic than the parent drug, as assessed by CLogP and HPLC methods. The chemical and enzymatic hydrolysis of these compounds was evaluated in aqueous buffer solution (pH 7.4) and 80% human plasma. All compounds showed a good chemical stability (t1/2 = 88-133 h) but underwent a rapid enzymatic hydrolysis to NAP (t1/2 around 3 h). The bioconversion of prodrugs into NAP was confirmed by an in vivo test, since i.p. administration of compounds 2-4 to mice gave a similar analgesic response than the parent drug. In vitro skin permeation experiments were performed using adult human SCE samples mounted in Franz-type diffusion cells. The butyl derivative 2 that showed an increased aqueous solubility compared to NAP gave a 5-fold improvement of skin permeation compared to NAP. In conclusion, the conjugate 2 could be regarded as a good candidate to improve NAP topical delivery and will be further studied as a prodrug for topical administration of this drug.