Α-hydroxyisovaleric Acid Research Articles

Synthesis of α-Hydroxyisovaleric acid (Hiv) and α-Acetyloxyisovaleric Acid (Ac-Hiv), Precursors of Aureobasidin B, with Improved Yield

α-Hydroxyisovaleric acid (Ac-Hiv) and α-acetyloxyisovaleric acid (Ac-Hiv) have been successfully synthesized through a diazotisation of amino acid using sodium nitrite with the catalyst of sulfuric acid and acetic acid, respectively. In the synthesis of Hiv, Zubia et al. (2005) mentioned that 3 equivalents of sodium nitrite for the reaction gave the hydroxy acid with a good yield. However, Cohen-Arazi et al. (2008) described that 6 equivalents of sodium nitrite resulted the highest yield. In present study, a variation of equivalents of sodium nitrite (3, 4, 5, 6 eq.) were trialed for the same method of synthesis. Through several experiments, we found that 6 equivalents of sodium nitrite were the best portion among all. This finding was applied into the synthesis of protected Hiv (Ac-Hiv) that was previously reported by Maharani et al. (2017) giving 63% yield when 3 equivalent of sodium nitrite was employed. By increasing the equivalent of sodium nitrite into 6 equivalents, the Ac-Hiv can be synthesized with an improved yield (71%).

A potential tool for diagnosis of male infertility: Plasma metabolomics based on GC–MS

Male infertility has become an important public health problem worldwide. Nowadays the diagnosis of male infertility frequently depends on the results of semen quality or requires more invasive surgical intervention. Therefore, it is necessary to develop a novel approach for early diagnosis of male infertility. According to the presence or absence of normal sexual function, the male infertility is classified into two phenotypes, erectile dysfunction (ED) and semen abnormalities (SA). The aim of this study was to investigate the GC–MS plasma profiles of infertile male having erectile dysfunction (ED) and having semen abnormalities (SA) and discover the potential biomarkers. The plasma samples from healthy controls (HC) (n=61) and infertility patients with ED (n=26) or with SA (n=44) were analyzed by gas chromatography–mass spectrometry (GC–MS) for discrimination and screening potential biomarkers. The partial least squares-discriminant analysis (PLS-DA) was performed on GC–MS dataset. The results showed that HC could be discriminated from infertile cases having SA (AUC=86.96%, sensitivity=78.69%, specificity=84.09%, accuracy=80.95%) and infertile cases having ED (AUC=94.33%, sensitivity=80.33%, specificity=100%, accuracy=87.36%). Some potential biomarkers were successfully discovered by two commonly used variable selection methods, variable importance on projection (VIP) and original coefficients of PLS-DA (β). 1,5-Anhydro-sorbitol and α-hydroxyisovaleric acid were identified as the potential biomarkers for distinguishing HC from the male infertility patients. Meanwhile, lactate, glutamate and cholesterol were the found to be the important variables to distinguish between patients with erectile dysfunction from those with semen abnormalities. The plasma metabolomics may be developed as a novel approach for fast, noninvasive, and acceptable diagnosis and characterization of male infertility.

Stereocomplexation between PLA-like substituted oligomers and the influence on the hydrolytic degradation

Stereocomplex formation was revealed between two PLA-like oligoester enantiomers. Two oligomeric enantiomers of each α-hydroxyisovaleric acid and lactic acid were synthesized and two part blends were prepared between all oligomer combinations. The blends were evaluated by DSC and XRD and a new crystal structure was detected in the case of d/l oligo-α-hydroxyisovaleric acid blend confirming stereocomplexation. Stereocomplexation was also verified for the D/L oligolactic acid blend. The two stereocomplexes had higher melting temperatures and increased enthalpy of melting compared to the pure oligomers. Hetero-stereocomplexation between different enantiomers of oligo(α-hydroxyisovaleric) acid and oligo(lactic acid) did not take place. The hydrolytic degradation rate was slower for the blends containing the more bulky and hydrophobic oligo(α-hydroxyisovaleric acid)s. Modifying PLA with this monomer could be used to reduce the degradation rate and at the same time modify the physical properties of PLA materials.

α-Ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain

Patients affected by maple syrup urine disease (MSUD) present severe neurological symptoms and brain abnormalities, whose pathoiphysiology is poorly known. In the present study we investigated the in vitro effects of leucine (Leu), α-ketoisocaproic acid (KIC) and α-hydroxyisovaleric acid (HIV), respectively, the branched-chain amino, keto and hydroxy acids that most accumulate in MSUD, on brain bioenergetic homeostasis, evaluating respiratory parameters obtained by oxygen consumption, membrane potential (∆Ψm), NAD(P)H content, swelling and citric acid cycle enzyme activities in mitochondrial preparations from rat forebrain using glutamate plus malate, succinate or α-ketoglutarate as respiratory substrates. KIC increased state 4 and decreased the respiratory control ratio with all substrates, in contrast with Leu and HIV. Furthermore, KIC and Leu, but not HIV, decreased state 3 using α-ketoglutarate. A KIC-induced selective inhibition of α-ketoglutarate dehydrogenase activity was also verified, with no alteration of the other citric acid cycle activities. The ADP/O ratio and the mitochondrial NAD(P)H levels were also reduced by KIC using glutamate/malate and α-ketoglutarate. In addition, KIC caused a reduction in the ∆Ψm when α-ketoglutarate was the substrate. Finally, KIC was not able to induce mitochondrial swelling. The present data indicate that KIC acts as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor possibly through its inhibitory effect on α-ketoglutarate dehydrogenase activity, while Leu acts as a metabolic inhibitor. It is suggested that impairment of mitochondrial homeostasis caused by the major metabolites accumulating in MSUD may be involved in the neuropathology of this disease.

Intrahippocampal administration of the branched-chain α-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 α-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 α-hydroxyisocaproic acid (HIC, 1.5 μmol), α-hydroxyisovaleric acid (HIV, 2.5 μmol), α-hydroxy-β-methyl-n-valeric acid (HMV, 1.5 μmol), or NaCl (2.5 μmol)(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 α-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 α-hydroxy acids accumulating in MSUD impair cognition and may be implicated in the neuropathology and psychomotor delay/mental retardation observed in the affected patients.

Solid phase synthesis of depsides and depsipeptides

A general solid phase methodology for the synthesis of depside and depsipeptide chains from optically active α-hydroxy acids and α-amino acids is reported. The automated preparation of depsides (97% yield per cycle) made up from the same enantiomer [i.e. H-[( S)-Man] 8-OH, 1] † † Abbreviations for α-hyroxy acids and depsides are consistent with those used for α-amino acids and peptides in the nomenclature of peptides, with “H” representing the hydroxy group and “OH” representing the carboxy group: H-Hiv-OH = α-hydroxyisovaleric acid; H-Lac-OH = lactic acid; H-Man-OH = mandelic acid. by both enantiomers [i.e. H-[( R)-Man-( S)-Man] 4-OH, 2], or by different hydroxy acids in the same chain [i.e. H-[( S)-Lac-( S)-Hiv] 3-OH, 3], and of depsipeptides where α-amino and α-hydroxy acids are alternatively introduced such as depsipeptide 6 (Cbz-[( S)-Val-( R)-Man-( R)-Val-( S)-Lac] 3-OH), are presented. Cyclization of the open chain depsides leads to chiral macrocycles whose structures resemble those of crown ethers.

Synthesis of a sterically congested α,α′-iminodiacid

The synthesis of iminodiacid 2, a derivative of valine, was found to be difficult at the point of attempting to functionalize the imino-nitrogen to form a tertiary amine. Nonetheless, a route was discovered starting from α-hydroxyisovaleric acid, ethanolamine and maleimide. After esterification, the α-triflate of α-hydroxyisovaleric acid was formed and used to sequentially alkylate the amino group of ethanolamine. Steric hindrance was reduced by tethering two of the amine substituents into lactone ring. This was followed by maleimide substitution of the hydroxyl group under Mitsunobu conditions.

Organic acids and branched‐chain amino acids in body fluids before and after multiple exchange transfusions in maple syrup urine disease

We successfully treated a critically ill infant with the classical type of maple syrup urine disease by multiple exchange transfusions via a peripheral artery and vein and with positive calorie supplementation in the early stage of therapy. Clinical improvement was definite after the plasma leucine level fell below 1 mmol/l. There was a close linear correlation between plasma concentrations of branched-chain amino acids and their corresponding branched-chain alpha-keto acids and branched-chain alpha-hydroxy acids. alpha-Hydroxy acids were more easily excreted in the urine than alpha-keto acids and amino acids. Our studies on urinary organic acids supported the existence of minor metabolic pathways of branched-chain alpha-keto acids, although they were not thought to be important in eliminating accumulated alpha-keto acids. Urinary excretion of succinic acid and alpha-ketoglutaric acid, which are components of the citric acid cycle, increased transiently during the patient's convalescence. The cerebrospinal fluid/plasma ratios for branched-chain amino acids, alpha-keto acids, and alpha-hydroxy acids were very high before the transfusions and decreased after improvement. The cerebrospinal fluid/plasma ratios for 5-carbon acids, alpha-ketoisovaleric acid and alpha-hydroxyisovaleric acid were much higher than for other branched-chain acids not only in the patient but also in normal controls. Cerebrospinal fluid levels of alpha-ketoisocaproic acid and alpha-hydroxyisovaleric acid were as high as 1 mmol/l in our patient.

Comparative Utilization of the α-Keto and d- and l-α-Hydroxy Analogs of Leucine, Isoleucine and Valine by Chicks and Rats

Several experiments were conducted to quantitatively evaluate the growth-promoting capacity of the isomers of the branched-chain amino acids (BCAA) and their α-hydroxy and α-keto analogs for the chick and rat. Basal chemically defined diets were formulated to be singly deficient in the BCAA under study; analogs therefore were evaluated as sources of supplemental amino acid activity. dl-Isoleucine (dl-Ile), α-keto-β-l-methylvaleric acid (KMV) and the isomers of α-hydroxy-β-methylvaleric acid (HMV) were inferior to an isomolar level of l-Ile and varied considerably in their capacity to support growth of chicks and rats. Efficacy values of the compounds for chicks (C) and rats (R) were: dl-Ile 85% (C), 58% (R); KMV 60% (C), 38% (R); l-HMV 84% (C), 65% (R); dl-HMV 49% (C), 45% (R); and d-HMV -10% (C), -2% (R). The isomers of valine (Val) and α-hydroxyisovaleric acid (HIV) had efficacy values in chicks of: dl-Val, 84%; d-Val, 72%; l-HIV, 82%; dl-HIV, 79%; d-HIV, 66%. d-Val had only marginal growth-promoting activity for rats, 16%. All Val analogs had comparable efficacy values for the rat: α-ketoisovaleric acid (KIV), 49%; l-HIV, 54%; dl-HIV, 51%; and d-HIV, 46%. dl-Leu and d-Leu, α-ketoisocaproic acid (KIC), and l-, dl- and d-α-hydroxyisocaproic acid (HIC) were all less efficacious than isomolar amounts of supplemental l-Leu in rats. Efficacy values were: dl-Leu, 78%; d-Leu, 48%; KIC, 56%; l-HIC, 58%; dl-HIC, 55%; and d-HIC, 41%. The BCAA keto analogs were not superior to the l-α-hydroxy analogs in growth-promoting capacity, and this is of great interest for the potential use of these nitrogen-free amino acid analogs in nutritional therapy.branched-chain amino acids leucine isoleucine valine branched-chain keto analogs branched-chain hydroxy analogs isomeric utilization analog efficacy

Synthesis and conformational analysis of polydepsipeptides

The synthesis and conformational analysis of several polydepsipeptides containing alkyl or polar residues are reported. Five separate routes to the synthesis of depsipeptide monomers and two methods of polymerization are decribed. Polydepsipeptides containing alanine, valine, leucine, lactic acid, α-hydroxyisovaleric acid, glutamic acid, and lysine were prepared and their conformations in solution analyzed. Helix-to-coil transitions for specific polydespsipeptides are obsurved in single organic solvents such as chloroform, tetrahydrofuran, or trifluoroethanol. A statistical thermodynamic theory of polymer melting successfully describes the observed transitions and allows quantitative determination of the tendency of specific amino acid residues to form helical arrays.

The conformational states of cyclopeptide systems. IX. Synthesis of cyclohexapeptides containing residues of N-methyl (amino acid)s and α-hydroxyisovaleric acid

The synthesis of ten cyclic hexapeptides containing residues of N-methyl (amino acid)s and of α-hydroxyisovaleric acid has been performed.

Synthesis and Biological Activity of Peptides Related to Eledoisin. III. C-Terminal Hexapeptide Amides Modified in Methionine and Isoleucine Residues

Abstract New analogs of hexapeptide related to eledoisin containing N-methylmethionine and α-hydroxy-γ-methylthiobutyric acid in place of the methionine, and α-hydroxyisovaleric acid in place of the isoleucine, were synthesized in order to obtain some information about the role of the amide bond in the peptide backbone. The former two were practically inactive in the rabbit pressure assay. These results indicated that the amide bond between the leucine and the methionine residues was important for the depressor activity of eledoisin. The last one showed very little activity. The results supported the suggestion made previously that the amide bond between the phenylalanine and the isoleucine residues is important in eliciting the biological response. The role of the amide bonds in the peptide backbone of eledoisin was also discussed.

The initiation of haemoglobin synthesis in rabbit reticulocytes.

1. The incorporation of labelled valine by rabbit reticulocytes into the N-terminal position of nascent haemoglobin was investigated by deaminating the nascent peptides with nitrous acid and isolating labelled alpha-hydroxyisovaleric acid and valine after acid hydrolysis. 2. The amount of radioactivity in alpha-hydroxyisovaleric acid relative to that in valine indicated the presence of 12.3% N-terminal valine having a free amino group. This high value suggests that most if not all nascent peptides contain valine in the N-terminal position. 3. Cell-free preparations containing reticulocyte ribosomes and pH5 enzymes incorporated alpha-hydroxy-[(14)C]isovaleryl-tRNA (where tRNA refers to transfer RNA), which was obtained by deamination of [(14)C]valyl-tRNA from yeast or liver with nitrous acid, into both soluble and nascent protein. 4. When the soluble protein was chromatographed on CM-cellulose, radioactivity was found to be associated with both the alpha-and beta-globin chains. 5. The kinetics of hydrolysis of [(14)C]valine, was also investigated. Most of the material was hydrolysed rapidly at pH10, but a minor component that was relatively stable appeared to be present to the extent of about 10% of the total valyl-tRNA. Valine was, however, the only hydrolysis product detected by paper chromatography. 6. It is concluded that chain initiation in haemoglobin synthesis involves valine as the N-terminal amino acid and that the amino group of nascent protein is probably not substituted.

Terpenoids—XLVI

Indian valerian root oil obtained from the roots of the plant V. wallichi collected from different areas has been examined. Neutral portion of the oil contains ar-curcumene, α,β,γ-patchoulenes, patchouli alcohol, β-sitosterol, valeranone, maali-oxide, maaliol, calarene, and the new sesquiterpene hydrocarbon β-bergamotene which is an isoprenologue of β-pinene. Acidic portion of the oil is composed of formic, propionic, butyric, isovaleric, β-methyl valeric, palmitic, steric acids, and isovaleryl ester of α-hydroxyisovaleric acid along with some unidentified acids.

Production of α-hydroxy fatty acids by two strains of Lactobacillus casei

The principal α-hydroxy acids other than lactic acid produced by L. casei strains 7469 and 280-16A were isolated by countercurrent extraction and identified as α-hydroxyisocaproic acid and α-hydroxyisovaleric acid. The amount of these acids and of lactic acid were estimated from counter-current distribution data, and the degrees of racemization were estimated from specific rotation values and from the results of optically specific microbiological assays. The maximal concentrations of α-hydroxyisocaproic and α-hydroxyisovaleric acids produced by L. casei were approximately 0.6 and 0.2 μeq./ml., respectively. The lactic acid, α-hydroxyisovaleric acid, and α-hydroxyisocaproic acid produced by L. casei 7469 were approximately 16%, 62%, and 97% racemic (the rest l-), respectively, whereas the same acids produced by L. casei 280-16A were much less racemic. This was particularly true of the L. casei 280-16A lactic acid, which appeared to be 99.3% l-lactic acid. Racemization of the α-hydroxy acids appears to be of importance in L. casei since strain 280-16A, which produces only slightly racemized acids, fails to grow in the usual media unless provided with a d-α-hydroxy acid source.

AMIDOMYCIN, A NEW ANTIBIOTIC FROM A STREPTOMYCES SPECIES, CHEMICAL STRUCTURE

Amidomycin, an antibiotic active primarily against yeast, has been isolated from a Streptomyces species. The Compound C10H68O12N4. is neutral, optically active, and shows no unsaturation nor characteristic light absorption maxima. It is composed of 4 moles each of D(−)-valine and D(−)-α-hydroxyisovaleric acid, linked alternately by ester and amide bonds to form a 24-membered ring (I). This structure is assigned from the following observations: on mild alkaline hydrolysis 4 moles of alkali are consumed with formation of a hydroxy acid, C10H19O4N (II). The latter on distillation gave a crystalline lactone, C10H17O3N, considered to be 3,6-diisopropyl-2,5-diketomorpholine (III), which was hydrolyzed to give 1 mole each of D(−)-valine and D(−)-α-hydroxyisovaleric acid.Amidomycin is closely related to valinomycin, an antibiotic isolated from Streptomycesfulvissimus and shown to be a 24-membered ring compound containing D(−)-valine, D(−)-α-hydroxyisovaleric acid, L(+)-valine, and L(−)-lactic acid. It also resembles the enniatins, produced by certain species of Fusarium, but differs from these compounds in the number of units in the ring structure as well as in containing D(−)-valine rather than an N-methyl-L-amino acid.

Antibiotics Produced by Fungi, and a New Phenomenon in Optical Resolution

IT was reported earlier1 that a strain of Fusarium lateritium produced an antibiotic, lateritiin-I, which was representative of a group of related compounds in presenting several remarkable chemical features. These features were elaborated in a communication to the Eleventh International Congress of Pure and Applied Chemistry held in London in July 1947, in which it was stated that lateritiin-I gave rise on hydrolysis to D(—)-α-hydroxyisovaleric acid and L(+)-N-methylvaline (II). The different configurations of these products were an indication, taking their configurational stabilities into account, that these units had an individual existence in the original antibiotic. This conclusion was supported by the isolation from lateritiin-I, after mild alkaline hydrolysis, of a lactone from which a crystalline methyl ester was prepared, the properties of these compounds being compatible with the structures (III) and (IV) respectively.