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PubMed2002

A convenient protocol for selective cleavage of 2-hydroxy acid amides. Application to semisynthesis of the cyclic heptapeptide aza HUN-7293.

A two-step protocol for the first chemoselective cleavage of 2-hydroxy acid amides has been developed. Mesylation of the model substrate 2-(hydroxypropionylamino)-4-methylpentanoic acid methyl ester (11) followed by treatment with N-ethylthiourea (13) allows cleavage of 2-hydroxy acid amides under smooth conditions. Successful application of this methodology to the open-chain transesterification product 15 (methylester) of the cyclic heptadepsipeptide HUN-7293, a potent inhibitor of inducible cell adhesion molecule expression, delivered the corresponding hexapeptide 18 with unprotected N-terminus in 70-75% yield. This result demonstrates that the protocol developed even works in the presence of an ester and several methylated and unmethylated amide bonds. Finally, a sequence of ligation of methyl D-dehydroglutaminate (20) to the C-terminus of the saponification product 21, followed by the degradation protocol and ring closure, allowed chemical "point mutation" at the DGCN site affording the aza analogue of HUN-7293 (24) in 15% overall yield. To the best of our knowledge this is the first report on chemoselective cleavage of 2-hydroxy acid amides.

Amides↗
PubMed2002

Absolute configuration of 3-hydroxy acids formed by Stenotrophomonas maltophilia: application of multidimensional gas chromatography and circular dichroism spectroscopy.

The soil bacterium Stenotrophomonas maltophilia was found to transform various long-chain fatty acids selectively into 3-hydroxy fatty acids of shorter chain length. Their chiral evaluation was performed by multidimensional gas chromatography (MDGC) on modified cyclodextrin phase comparing the enantiodistribution of 1,3-diol formed without loss of stereochemical information from a representative microbial product with those of synthetic (3RS)- and (3S)-1,3-diols. Enantiomeric excesses of 84-98% (R) were determined for the microbially produced 3-hydroxy acids. In addition, the CD exciton chirality method was applied to determine their absolute configuration. Derivatization with 9-anthryldiazomethane and 2-naphthoylimidazole led to the required bichromophoric structures. Their CD spectra displayed a positive first Cotton effect around 254 nm and a negative second Cotton effect around 237 nm, which confirmed the (R)-configuration of the bacterial products.

Biotransformation↗
PubMed2002

Effects of alpha- and beta-hydroxy acids on the edemal response induced in female SKH-1 mice by simulated solar light.

alpha- and beta-Hydroxy acids have been used extensively in cosmetic and dermatological formulations. At present, there is an inadequate amount of information with which to assess the safety of topical applications of alpha- and beta-hydroxy acids in conjunction with exposure to ultraviolet light. In the present study, we examined changes in the epidermal basal cell proliferation and the edemal response using skin thickness measurements elicited in SKH-1 mice following exposure to simulated solar light (SSL) with or without topical treatment with creams containing alpha- (glycolic) and beta-hydroxy (salicylic) acids. The dose of SSL light required to induce measurable edema (MED(BIOL)) in nai;ve, free-moving SKH-1 mice was determined to be 90 mJ. CIE/cm(2). Pretreating the mice with daily (5 days/week) exposures of 14 mJ. CIE/cm(2) for 6 weeks resulted in a doubling of the MED(BIOL) to 180 mJ. CIE/cm(2). Topical application of control cream (pH 3.5), or creams containing glycolic acid (10%, pH 3.5) or salicylic acid (4%, pH 3.5) for 6 weeks (5 days/week) increased the MED(BIOL) to 137 mJ. CIE/cm(2). Daily treatments with SSL (14 mJ. CIE/cm(2)) and control cream (pH 3.5), glycolic (10%, pH 3.5) or salicylic (4%, pH 3.5) acid-containing creams for 6 weeks (5 days/week) resulted in an MED(BIOL) value of 180 mJ. CIE/cm(2), which was the same as treatment with light alone for 6 weeks. These data indicate that a 6-week treatment of mouse skin with a representative skin cream, with or without representative alpha- and beta-hydroxy acids (glycolic and salicylic acid, respectively), changes the UV light sensitivity; however, treatment with the cream, with or without the acids, does not contribute to the UV sensitivity of mice cotreated with low doses of UV light.

Administration, Topical↗
PubMed2003

Role of the charge in continuous beds in the chiral separation of hydroxy acids by ligand-exchange capillary electrochromatography.

This paper deals with the chiral separation of hydroxy acids using diallyl-dimethylammonium chloride as a positive charge-providing agent in the continuous bed. The chiral continuous bed was prepared by in situ copolymerization of monomers, including an L-4-hydroxyproline derivative as a chiral selector. This phase was applied to the chiral separation of hydroxy monocarboxylic acids and hydroxy dicarboxylic acids, respectively. The influence of both the selector concentration and the charge-providing agent on retention and separation was investigated.

Chromatography, Ion Exchange↗
PubMed2001

High-performance liquid chromatographic technique for the simultaneous determination of lactone and hydroxy acid forms of camptothecin and SN-38 in tissue culture media and cancer cells.

Analysis of camptothecins in biologic media is hampered by chemical hydrolysis of the parent lactone (form I) to an inactive hydroxy acid (form II). A solid-phase extraction (SPE) method utilizing C2-bonded silica particles (100 mg, 1 ml) is presented for simultaneous determination of forms I and II of camptothecin (CPT) and SN-38 (active metabolite of clinically used CPT-11) in culture media and cell lysates. A new HPLC separation is described that efficiently resolves all four compounds employing gradient elution with 10 mM ammonium acetate, increasing methanol (20-80% over 15 min), and a 15-cm by 3-mm Symmetry Shield (RP8) column. Components were detected by fluorescence at an excitation wavelength of 380 nm and emission wavelength of 423 nm. Lactones were shown to be unstable at alkaline pH and hydroxy acids unstable at alkaline pH while the following conditions preserved the chemical equilibrium in specimens: samples kept on ice, final pH of eluates 7.4, autosampler temperature 4 degrees C, and analysis cycle <4 h. Quantitative recovery of lactones was achieved from RPMI culture medium over a wide concentration range (93.5-111.6% for 1-400 ng/ml) although greater variability was noted with the hydroxy acids (59.6-110.3%, 1-400 ng/ml). Limit of quantitation (precision and accuracy <20%) was 0.2 ng/ml for CPT lactone, 0.5 ng/ml for SN-38 lactone, and 2 ng/ml for the two hydroxy acids. The method was applied to quantitate the accumulation of SN-38 and CPT (form I and II) in HT29 and HCT116 human colon cancer cells.

Camptothecin↗
PubMed2006

Characterization of the cereulide NRPS alpha-hydroxy acid specifying modules: activation of alpha-keto acids and chiral reduction on the assembly line.

Several nonribosomal peptide natural products are composites of alpha-hydroxy acid and alpha-amino acid monomers. Cereulide, the emetic toxin from the human pathogen Bacillus cereus, and valinomycin, from Streptomyces spp., are closely related macrocyclic K+ ionophores. The macrocyclic core of each natural product contains alternating peptide (six) and ester (six) bonds, and their cyclododecadepsipeptide structures consist of a tetradepsipeptide unit repeated three times. Here we overexpress the cereulide NRPS alpha-hydroxy acid specifying modules from CesA and CesB and demonstrate that each contains an alpha-keto acid activating adenylation domain and a chiral alpha-ketoacyl-S-carrier protein reductase (alpha-KR). The logic used by the cereulide NRPS is likely at work in the valinomycin NRPS and may be the general strategy used in bacterial NRPSs to form alpha-hydroxy acid containing natural products.

Depsipeptides↗
PubMed2001

Oxidation-active flavin models: oxidation of alpha-hydroxy acids by benzo-dipteridine bearing metal-binding site in the presence of divalent metal ion and base in organic solvents.

The oxidizing ability of benzo-dipteridine bearing a bipyridin-6-ylmethyl moiety (4) was found to be increased with Zn(2+) by approximately 10(3)-fold for sulfite addition in MeOH and approximately 10(2)-fold for oxidation of an NADH model in MeCN. It was found for the first time that 4 is able to oxidize alpha-hydroxy acids to alpha-keto acids in the presence of a divalent metal ion such as Zn(2+), Co(2+), and Ni(2+) and an amine base in MeCN or t-BuOH, whereas benzo-dipteridine having a bipyridin-5-ylmethyl moiety (3) is unable to oxidize them under the same conditions. The oxidation reaction was kinetically investigated including the kinetic isotope effect for deuterated mandelic acids (k(H)/k(D) = 2.1-3.7) and the Hammett plots for substituted mandelic acids (V-shaped plots). In the reaction of alpha-substituted alpha-hydroxy acids such as alpha-methyl mandelic and benzylic acids with 4, novel oxidative decarboxylation was found to take place, giving acetophenone and benzophenone, respectively. The oxidation mechanism for mandelic acid was proposed to proceed via a ternary complex of 4.Zn(2+).PhCH(OH)CO(2)(-), in which alpha-oxyanion of mandelate attacks C(4a)-position of 4 to form an adduct followed by 1,2-elimination to afford benzoyl formate and 2e-reduced 4. The roles of the metal ion were proposed as follows; (i) activation of 4, (ii) substrate-binding site, and (iii) activation of the bound alpha-hydroxy acid by lowering pK(a)'s of alpha-OH and alpha-CH. This is a first example that a flavin model oxidizes alpha-hydroxy acids in the presence of a metal ion.

Journal Article↗
PubMed1998

Synthesis of 2-hydroxy acid from 2-amino acid by Clostridium butyricum.

Cultures of Clostridium butyricum type strain in synthetic medium supplemented with various L-2-amino acids revealed the presence of the corresponding 2-hydroxy acid. This metabolite is able to produce the polyester poly(2-hydroxyalkanoic acid). The bioconversion is not stereoselective since D-2-amino acids were also converted. Chiral GC analysis demonstrated that only D-enantiomer is formed from L-leucine.

Amino Acids↗
PubMed1996

Increased factor XIIIa transglutaminase expression in dermal dendrocytes after treatment with alpha-hydroxy acids: potential physiologic significance.

BACKGROUND: Topical alpha-hydroxy acids (AHAs) have been shown to improve photoaging in human skin. OBJECTIVE: We studied factor XIIIa transglutaminase expression in dermal dendrocytes (DDs) and mast cell degranulation after treatment of the skin with AHAs. METHODS: Skin biopsy specimens obtained from patients after 4 to 8 months of treatment with lotions containing 25% AHAs were evaluated for factor XIIIa transglutaminase expression with immunoperoxidase and electron microscopy. Immunoperoxidase-stained sections were studied by means of semiquantitative methods and image analysis. Mast cell degranulation was studied by image analysis. RESULTS: Increased factor XIIIa transglutaminase expression was seen after treatment with AHAs. All treated sites had increased scores compared with control sites by semiquantitative methods. Seventy-five percent of treated sites showed an increased mean area over control sites of factor XIIIa transglutaminase positivity with image analysis. These results correlated with an increased level of mast cell degranulation in treated sites and with activation of DDs as seen by electron microscopy. CONCLUSION: Treatment of the skin with AHAs leads to mast cell degranulation and increased expression of factor XIIIa transglutaminase by activated DDs. Mast cell degranulation may lead to activation of DDs and increased factor XIIIa transglutaminase expression, via the action of tumor necrosis factor-alpha. We speculate that clinical and histologic improvement in photoaged skin after treatment with AHAs may be somehow related to this process.

Administration, Cutaneous↗
PubMed1997

Injectable microcapsules prepared with biodegradable poly(alpha-hydroxy) acids for prolonged release of drugs.

In this paper, microencapsulation techniques for the preparation of drug-containing monolithic microcapsules for prolonged release using biodegradable poly(alpha-hydroxy) acids, such as polylactic acid, poly(lactide-co-glycolide) and copoly(lactic/glycolic) acid are reviewed. Phase separation, solvent evaporation, and spray drying procedures are discussed. In order to achieve controlled-release formulations of highly water-soluble drugs that are entrapped efficiently, various manufacturing techniques and procedures have been developed. Degradation of poly(alpha-hydroxy) acids is altered by the copolymer ratio and molecular weight of the polymer used to make microcapsules and the amounts of released microencapsulated drugs correlate almost linearly with polymer degradation, indicating that controlled-release formulations, which release drugs over different times, can be prepared using suitable poly(alpha-hydroxy) acids with different degradation rates.

Biocompatible Materials↗
PubMed2000

Enantiomeric separation and discrimination of 2-hydroxy acids as O-trifluoroacetylated (S)-(+)-3-methyl-2-butyl esters by achiral dual-capillary column gas chromatography.

An efficient method is described for the simultaneous enantiomeric separation of 18 different racemic 2-hydroxy acids for the determination of their absolute configurations. It involves the conversion of each enantiomer into a diastereomeric O-trifluoroacetylated (S)-(+)-3-methyl-2-butyl ester for the direct separation by achiral dual-capillary column gas chromatography with subsequent identification and determination of its chirality by retention index (I) library matching. The enantiomers of each acid were well separated with high resolution values (R > or = 1.4) on DB-5 and DB-17 columns of different polarity. When temperature-programmed I values of 2-hydroxy acid enantiomers as their diastereomeric derivatives were measured on both columns, the I values were characteristic of each enantiomer. Simple I matching with the reference values was thus useful in cross-checking each acid enantiomer for the identification and chiral discrimination. When applied to urine samples, the present method allowed positive identification of most of the spiked 2-hydroxy acids from normal urine and for endogenous (S)-lactic acid and (S)-2-hydroxybutyric acid from a clinical urine specimen.

Chromatography, Gas↗
PubMed1985

Urinary glycolate measured by use of (S)-2-hydroxy-acid oxidase.

Glycolate can be determined in urine by using (S)-2-hydroxy-acid oxidase (EC 1.1.3.15; formerly called "glycolate oxidase"), either immobilized in a continuous-flow system or in a semiautomated procedure for the centrifugal analyzer. In the presence of peroxidase (EC 1.11.1.7), the hydrogen peroxide formed from glycolate is detected by use of a peroxide indicator reaction. Before the analysis, urine must be treated with charcoal to remove reducing substances such as ascorbic acid, which interfere with the assay by decreasing the color of the indicator reaction. Lactate also interferes with the determination of glycolate because it also is a substrate for this oxidase; thus a correction has to be made for the lactate content of urine. The system with (S)-2-hydroxy-acid oxidase immobilized to the inner surface of nylon tubing is accurate, precise, and sensitive but unsuitable for routine use because, even immobilized, the oxidase is unstable and can only be used for 12 days. We have used the semiautomated assay routinely: it has a mean analytical recovery of 96% (SD 4.2%), a within-batch CV less than 2%, and a between-batch CV less than 5%. The normal reference interval for urinary excretion of glycolate so measured is 0.13 to 1.31 mmol per day (n = 55).

Alcohol Oxidoreductases↗
PubMed1969

Assay, purification and properties of mammalian D-2-hydroxy acid dehydrogenase.

1. A new method is described for the measurement of d-2-hydroxy acid dehydrogenase in samples of animal tissues. 2. The distribution of the enzyme in a number of animals was determined. Of the animal tissues tested, the most active source of the enzyme was found to be rabbit kidney cortex. 3. The enzyme was purified from rabbit kidney to a stage at which it appears to be homogeneous in the analytical ultracentrifuge and on polyacrylamide-gel electrophoresis. 4. The molecular weight was estimated by gel filtration to be approx. 102000; combination of gelfiltration data and the sedimentation coefficient gave a value of 95000. 5. The purified enzyme has a spectrum typical of a flavoprotein. The change induced in the spectrum on addition of d-malate or d-lactate suggests the formation of a flavin semiquinone. 6. Flavin can be removed by treatment with acid ammonium sulphate, and activity can be restored to the inactive apoenzyme by addition of FAD, but not of FMN or riboflavin. 7. Studies of acceptor specificity showed that the enzyme has a relatively weak d-2-hydroxy acid oxidase activity.

Alcohol Oxidoreductases↗
PubMed1995

Further study on the use of uncharged beta-cyclodextrin polymer in capillary electrophoresis: enantiomeric separation of some alpha-hydroxy acids.

Uncharged beta-cyclodextrin polymer was used as chiral selector for the enantiomeric separation of some alpha-hydroxy acids by capillary electrophoresis. Complexation and enantiomeric resolution of mandelic acid, m-hydroxy and p-hydroxymandelic acid, 3,4-dihydroxymandelic acid, as well as 2- and 3-phenyllactic acid were studied, changing the concentration of the beta-cyclodextrin polymer added to the background electrolyte at different pH in the range of 4.5-7. Furthermore, the effects of the concentration of the background electrolyte, column temperature, and applied voltage on chiral resolution were also examined. The best enantiomeric separations were obtained using a background electrolyte at pH 6 containing 100 mg/mL of beta-cyclodextrin polymer.

Cyclodextrins↗
PubMed1999

Histamine-modified cationic beta-cyclodextrins as chiral selectors for the enantiomeric separation of hydroxy acids and carboxylic acids by capillary electrophoresis.

The enantiomeric separation of alpha-hydroxy acids and carboxylic acids was successfully performed by using 6-deoxy-6-N-histamino-beta-cyclodextrin (CD-hm), a monosubstituted positively charged beta-cyclodextrin (beta-CD) bearing a histamine moiety linked to the C6 of a glucose unit in the upper CD rim via the amino group. Good results were obtained at a low selector concentration (1 mM). The number of positive charges on the upper rim may be modulated as a function of pH, because of the different pKa of the amino and the imidazolyl groups, and was found to affect both the enantioselectivity and resolution factors. With the analogous 6-deoxy-[4-(2-aminoethyl)imidazolyl]-beta-cyclodextrin (CD-mh) bearing the histamine moiety linked to the C6 via the imidazolyl group, very poor results were obtained, showing that the proximity of the positive charge to the cavity plays an important role in the enantiomeric recognition. The complexation mode was studied by electrospray ionization-mass spectrometry (ESI-MS) and two-dimensional nuclear magnetic resonance (2-D NMR) ROESY experiments: the recognition model is consistent with an inclusion complexation of the aromatic ring of the analyte within the CD cavity coupled to electrostatic interactions between the carboxylate and the protonated amino group of the cyclodextrin.

Carboxylic Acids↗
PubMed2005

Intrahippocampal administration of the branched-chain alpha-hydroxy acids accumulating in maple syrup urine disease compromises rat performance in aversive and non-aversive behavioral tasks.

Maple syrup urine disease (MSUD) is an inherited metabolic disease predominantly characterized by neurological dysfunction. Although a variable degree of psychomotor/delay/mental retardation is found in a considerable number of MSUD patients, the mechanisms underlying the neuropathology of this disorder are yet not defined. The present study investigated the effect of acute intrahippocampal administration of the branched-chain alpha-hydroxy acids (BCHA) accumulating in MSUD on rat behavior in non-aversive (open field) and aversive (inhibitory avoidance) tasks. Cannulated 60-day-old male Wistar rats received bilateral intrahippocampal injection of alpha-hydroxyisocaproic acid (HIC, 1.5 micromol), alpha-hydroxyisovaleric acid (HIV, 2.5 micromol), alpha-hydroxy-beta-methyl-n-valeric acid (HMV, 1.5 micromol), or NaCl (2.5 micromol)(controls) immediately after or 10 min before training. Testing session was performed 24 h later. Administration of the hydroxy acids immediately after training caused no effect on the cognitive performance of the rats. In contrast, HIV and HMV administered 10 min before training provoked a habituation deficit in the open field task. Motor activity, assessed by crossing responses, was the same for the groups infused with BCHA and NaCl. The effect of MK-801, succinate, creatine, and the antioxidants ascorbic acid plus alpha-tocopherol on the behavioral alterations provoked by HIV in the open field task revealed that only the energetic substrates (succinate and creatine) prevented these effects, reflecting a possible compromise of brain energy production by HIV. We also observed that rats pretreated with HIC, HIV, or HMV did not increase their latency in the testing session in the step-down inhibitory avoidance task, revealing an impairment of retrieval (memory retention or acquisition) in this task. Furthermore, no differences between controls and rats receiving BCHA were detected in the latency to leave the platform in the training test, suggesting similar motor activity of all groups. The data indicate that the alpha-hydroxy acids accumulating in MSUD impair cognition and may be implicated in the neuropathology and psychomotor delay/mental retardation observed in the affected patients.

Animals↗