- Catalytic Oxidation of Dithiols by a Semisynthetic Enzyme
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The semisynthetic enzyme flavopapain (1C), obtained from the alkylation of Cys-25 of papain with 8α-(bromoacetyl)-10-methylisoalloxazine (1B), was found to be an effective catalyst for the oxidation of dithiols to disulfides.The k2/Ks values for the oxidation of d,l-dihydrolipoamide and d,l-dihydrolipoic acid determined from anaerobic single-reaction stopped-flow kinetics were 4400 and 3400 M-1 s-1, respectively.These values were, respectively, 126 and 200 times larger than the second-order rate constants for oxidation of d,l-dihydrolipoamide and d,l-dihydrolipoic acid by the model flavin 8-acetyl-10-methylisoalloxazine (1A).Under aerobic turnover conditions using the synthetic dye MTT as an electron acceptor, the kcat and Km values for the oxidation of d,l-dihydrolipoamide by 1C were in approximate agreement with the k2 and Ks values, indicating that the rate-limiting step of catalytic cycle is substrate oxidation rather than oxidation of dihydroflavopapain.When compared with flavopapains 2C and 3C , flavopapain 1C is the most efficient catalyst.The circular dichroic spectra of flavopapains 1C, 2C and 3C were recorded, and the dissociation constants of the sulfite addition complexes of 1C and 2C were determined.From these kinetic and physical studies, the differences in catalytic activity of 1C, 2C, and 3C were judged to be due to changes in the flavin orientation within the active site and the ability to fit the substrate into a productive reaction conformation.
- Stewart, Kent D.,Radziejewski, Czestaw,Kaiser, E. T.
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- A Reagent for Reduction of Disulfide Bonds in Proteins That Reduces Disulfide Bonds Faster Than Does Dithiothreitol
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We have synthesized a new reagent - N,N'-dimethyl-N,N'-bis(mercaptoacetyl)hydrazine (DMH) - for the reduction of disulfide bonds in proteins.DMH reduces disulfide bonds 7 times faster than does dithiothreitol (DTT) in water at pH 7.DMH reduces mixed disulfides of cysteine proteases (papain and ficin) especially rapidly (30 times faster than DTT).DMH (ε0 = -0.300 V) reduces noncyclic disulfides completely, although it is less strongly reducing than DTT (ε0 = -0.356 V).
- Singh, Rajeeva,Whitesides, George M.
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- Equilibrium Constants for Thiol-Disulfide Interchange Reactions: A Coherent, Corrected Set
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Equilibrium constants (Keq) for the thiol-disulfide interchange reactions between dithiothreitol (DTT) and lipoic acid (14.2 +/- 0.7), lipoic acid (Lip) and mercaptoethanol (13.3 M +/- 1.0 M), and mercaptoethanol (ME) and glutathione (GSH or GSSG) (1.20 +/- 0.10) were measured in D2O at pD 7.0 by 1H NMR spectroscopy.Two of these equilibrium constants were also measured in D2O/CD3OD.These values are compared with those obtained by other methods.A coherent set of values for the equilibrium constants between DTT or ME and thiols having a range of structures was assembled (Table III).The recommended value for the equilibrium constant between DTT and GSH is 210 M (Keq = ox>2/(red>)).
- Lees, Watson J.,Whitesides, George M.
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- Thiolates of arsenic(III), antimony(III), and bismuth(III) with dl-α-dihydrolipoic acid
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Lipoic acid can be reduced to dihydrolipoic acid free of lipoic acid without using deoxygenated solvents. Dihydrolipoic acid reacted with phenylarsine oxide, As2O3, and AsCl3, SbCl 3 but not Sb2O3, and Bi2O 3, BiCl3, and Bi(NO3)3· 5H2O in various solvents giving thiolates. When the reactions were done in methanol, the HCl and HNO3 released caused esterification of the -COOH group. The reaction with As(III) compounds was sensitive to dioxygen, leading to production of lipoic acid derivatives as well, arsenite being particularly active for the autoxidation. Physical (1H NMR) and chemical [reactivity of >M-Cl and >Bi(NO3)] properties of the adducts are described. The six-membered dihydrolipoic acid complexes reacted with stoichiometric amounts of British Anti-Lewisite releasing the dihydrolipoic acid by forming the corresponding complexes of British Anti-Lewisite. Graphical Abstract: [Figure not available: see fulltext.]
- Ioannou, Panayiotis V.,Tsivgoulis, Gerasimos M.
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- A lipoic acid injection and its preparation method (by machine translation)
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The present invention to provide a high safety of the thioctic acid preparation, including lipoic acid, the solvent component, characterized in that the vinyl octoate in preparation, containing lipoic acid ethylenediamine double-substituent, wherein the lipoic acid ethylenediamine double-substituent content are not higher than 0.2%. The lipoic acid preparation high safety, low toxicity, can be better clinical efficacy of lipoic acid. (by machine translation)
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Paragraph 0076-0081
(2019/07/04)
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- Preparation method of R-(+)-lipoic acid
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The invention discloses a preparation method of R-(+)-lipoic acid. The method comprises the following steps: performing salt formation on a raw material of racemic lipoic acid and a resolving agent ofR-phenylethylamine, so as to obtain diastereoisomeric R-phenylethylamine racemic lipoic acid salt; performing recrystallization separation on a raw material of the salt, so as to obtain a single enantiomer of R-phenylethylamine R-(+)-lipoic acid salt; finally, acidizing the single enantiomer of R-phenylethylamine R-(+)-lipoic acid salt, so as to obtain the target compound R-(+)-lipoic acid in a structure of the formula (I) at a yield of 40%. The method is simple in operation, lower in requirements on equipment, mild in conditions and higher in yield, so that the method is suitable for industrial production.
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Paragraph 0038; 0043; 0044; 0046; 0050; 0052; 0054
(2018/06/23)
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- Oxidation-triggered aggregation of gold nanoparticles for naked-eye detection of hydrogen peroxide
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Naked-eye detection of H2O2 was realized based on the color change of gold nanoparticles upon aggregation. The removal of polyethylene glycol chains from the nanoparticle surface under H2O2 treatment let to the exposure of inner hydrophobic ligands, causing the nanoparticle aggregation in aqueous medium. This detection system shows a wide dynamic range in the μM scale and a distinguishable limit of 10 μM.
- Wu, Shaojue,Tan, Si Yu,Ang, Chung Yen,Luo, Zhong,Zhao, Yanli
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p. 3508 - 3511
(2016/03/04)
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- Chirality induction and chiron approaches to enantioselective total synthesis of α-lipoic acid
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Abstract An efficient, short and convenient asymmetric synthesis of (R)-(+)-lipoic acid in seven steps from chiral hydroxy aldehyde with 32.5% overall yield is described. Synthesis of S and R enantiomers of α-lipoic acid from cis-1,4-butene diol derived chiral lactone is reported with 34 % overall yield. The present synthesis involves use of simple reaction conditions making it a convenient synthesis.
- Chavan, Subhash P.,Pawar, Kailash P.,Praveen, Ch.,Patil, Niteen B.
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p. 4213 - 4218
(2015/06/02)
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- Polyphenolic Bioprecursors
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Cosmetic and therapeutic, in particular dermatological bioprecursors have the formula [A]n—PP—[B]m wherein PP is a polyphenol radical in which each hydroxyl function is protected by a group A or a group B, A is a saturated or unsaturated, substituted or unsubstituted alkyl radical having 1 to 20 carbon atoms which is bonded to the polyphenol, n is an integer not less than 1, and B is a precursor of a biologically active molecule, which is also bonded to the polyphenol, and m is an integer also not less than 1.
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Page/Page column 9-10
(2009/09/07)
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- Process For Purifying Thioctic Acid in Water
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Process for purifying thioctic acid in water comprising the following steps: a) dissolving the thioctic acid in an aqueous alkaline solution or alternatively dissolving a thioctic acid salt, if necessary adjusting the pH to alkaline values, b) acidifying the solution from step (a) with an acid chosen from the class consisting of sulfuric acid, phosphoric acid, methanesulfonic acid to a pH between 5.4 and 5.8. c) isolating the thioctic acid precipitated in step (b) by conventional methods.
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Page/Page column 2
(2008/12/07)
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- NOVEL LIPOIC ACID CONJUGATED COMPOUNDS AND SKIN EXTERNAL APPLICATIONS CONTAINING THEREOF
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The present invention relates to derivatives of lipoic acid and skin external applications containing thereof that represent whitening effect, soothing effect, anti-aging effect and acne- improving effect and preventing effects of bladness disorder and seborrheic skin disorder.
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Page/Page column 27-28
(2008/06/13)
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- PROCESS FOR PURIFYING THIOCTIC ACID IN WATER
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Process for purifying thioctic acid in water comprising the following steps: a) dissolving the thioctic acid in an aqueous alkaline solution or alternatively dissolving a thioctic acid salt, if necessary adjusting the pH to alkaline values, b) acidifying the solution from step (a) with an acid chosen from the class consisting of sulfuric acid, phosphoric acid, methanesulfonic acid to a pH between 5.4 and 5.8. c) isolating the thioctic acid precipitated in step (b) by conventional methods.
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Page/Page column 3-4
(2008/06/13)
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- Simplistic expedient and practical synthesis of (±)-α-lipoic acid
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Synthesis of α-lipoic acid has been achieved by a simple sequence of reactions. The synthesis highlights the use of α-chloroesters in a Reformatsky reaction. The intermediate keto acid is an intermediate from which both isomers of lipoic acid can be prepared. Georg Thieme Verlag Stuttgart.
- Chavan, Subhash P.,Shivsankar,Pasupathy
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p. 1297 - 1300
(2007/10/03)
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- A facile regioselective decomposition of tosylhydrazones: An application towards the synthesis of α-lipoic acid
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A facile regioselective decomposition of tosylhydrazones using NaOH as a base in refluxing isopropyl alcohol is described. This finding has been successfully applied towards the synthesis of (±)-α-lipoic acid (1).
- Chavan, Subhash P.,Kale, Ramesh R.,Pasupathy
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p. 1129 - 1132
(2007/10/03)
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- Therapeutic compositions containing oligo (ethylene glycol)-terminated 1,2-dithiolanes and their conjugates
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The present invention provides biotechnologically useful oligo(ethylene glycol)-terminated 1,2-dithiolane compositions and conjugates of these compositions with biological or non-biological receptor, ligand, sequestering, or reporter moieties to provide physiologically active therapeutic compositions. The invention also provides methods for the preparation of these compositions. Further, the invention provides self-assembled monolayer (SAM) compositions on a metal and methods for their preparation.
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- Enantioselective synthesis of R-(+)-α and S-(-)-α-lipoic acid
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An efficient synthesis of α-lipoic acid from the readily available cis-2-butene-1,4-diol employing a Claisen orthoester rearrangement and Sharpless asymmetric dihydroxylation as the key steps, is described.
- Chavan, Subhash P.,Praveen, Cherukupally,Ramakrishna,Kalkote
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p. 6027 - 6028
(2007/10/03)
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- The synthesis of R (+) α-lipoamino acid
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Process for the synthesis of R(+)alpha-lipoic acid comprising the following stages: a) Salifying of racemic 6,8-halo-octanoic acid with S(-)alpha-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(-)alpha-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(-)alpha-methylbenzylamine; (d) separation of the diastereoisomeric salt to obtain R(+)6,8-di-halo-octanoic acid by reation of said salt with strong mineral acids in an aqueous solution with a dilution between 2 and 10% by weight; e) esterification of R(+)6,8-di-halo-octanoic acid to obtain the corresponding alkyl ester; f) reaction of the alkyl ester of R(+)6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis; g) hydolysis of the ester of R(+)alpha-lipoic acid.
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- Oligo(ethylene glycol)-terminated 1,2-dithiolanes and their conjugates useful for preparing self-assembled monolayers
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The present invention provides biotechnologically useful oligo(ethylene glycol)-terminated 1,2-dithiolane compositions and conjugates of these compositions with biological or non-biological receptor, ligand, sequestering, or reporter moieties. The invention also provides methods for the preparation of these compositions. Further, the invention provides self-assembled monolayer (SAM) compositions on a metal and methods for their preparation.
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- Compositions and methods for prevention and treatment of chronic diseases and disorders including the complications of diabetes mellitus
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This invention relates to nutrient and therapeutic compositions for treatment and prevention of symptoms and disease conditions associated with microangiopathy and macroangiopathy and to methods using the compositions. In particular, the invention relates to compositions useful in the treatment of diabetic retinopathy and nephropathy, to compositions useful in the treatment of other retinal disorders including macular degeneration and cataracts, to compositions useful in wound healing, to compositions useful for treatment and prevention of neuropathy, to compositions useful for treatment and prevention of cardiovascular disease and to compositions useful for the treatment and prevention of dental and periodontal disorders.
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- Asymmetric dihydroxylation and hydrogenation approaches to the enantioselective synthesis of R-(+)-α-lipoic acid
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The asymmetric synthesis of methyl (S)-6,8-dihydroxyoctanoate (5) and (S)-6,8-dimethylsulfonyloxyoctane-1-carboxylic acid (13), key precursors to R-(+)-α-lipoic acid (6) is described using OsO4-catalyzed asymmetric dihydroxylation and Ru-catalyzed asymmetric hydrogenation, respectively, as the key steps in the reaction sequence. These methods lead to an efficient formal synthesis of R-(+)-α-lipoic acid in 90% ee.
- Upadhya,Nikalje,Sudalai
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p. 4891 - 4893
(2007/10/03)
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- A short and productive synthesis of racemic α-lipoic acid
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Racemic α-lipoic acid is synthesized in four steps from the base chemicals vinyl ethyl ether and cyclohexanone. The total yield is 40%.
- Balkenhohl, Friedhelm,Paust, Joachim
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p. 649 - 654
(2007/10/03)
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- Lipase catalyzed regio- and stereospecific hydrolysis: Chemoenzymatic synthesis of both (R)- and (S)-enantiomers of α-lipoic acid
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Native lipase of Candida rugosa (EC 3.1.1.3) enantioselectively and regiospecifically hydrolyses the n-butyl ester of 2,4-dithioacetyl butanoic acid either at the carboxylic acid terminus or at the α-thioacetate to provide enantiomerically pure (R)-2,4-dithioacetyl butyric acid and (S)- butyl 2-thio-4-thioacetyl butyrate (ee >98%) while the lipase modified by treatment with diethyl p-nitrophenyl phosphate attacks only the α- thioacetate giving enantiomerically pure (S)-butyl 2-thio-4-thioacetyl butyrate. These enantiomerically pure intermediates can be used as chiral building blocks to obtain both(S)- and (R)-enantiomers of α-lipoic acid and their analogues.
- Fadnavis,Babu, Ravi Luke,Vadivel, S. Kumara,Deshpande, Ashlesha A.,Bhalerao
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p. 4109 - 4112
(2007/10/03)
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- Models for the inhibition of dithiol-containing enzymes by organoarsenic compounds: synthetic routes and the structure of [PhAs(HlipS2)] (HlipS22- = reduced lipoic acid)
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The arsenic(III) dithiolate [PhAs(HlipS2)] (1, HlipS22- = reduced rac-lipoic acid) has been obtained via three different routes: (A) from (PhAsO)n and rac-dihydrolipoic acid, (B) from (AsPh)6 and rac-lipoic acid, and (C) from PhAsO(OH)2 and rac-dihydrolipoic acid. The latter method is also suitable for the preparation of [(4-NH2C6H4)As(HlipS2)] (2) from (4-NH2C6H4)AsO(OH)2. rac-Dihydrolipoic acid and Me2-AsO(OH) react to give [(Me2As)2(HlipS2)] (3). These reactions indicate pathways by which mono- and diorganoarsenic compounds of various As oxidation states (I, III, and V) may inhibit enzymes that contain lipoic acid as a cofactor. X-ray structure analysis shows that 1 is a 2,4-disubstituted 1,3,2-dithiarsinane, i. e. a six-membered heterocycle. The phenyl group at the 2-position (As) adopts the axial orientation. (2RS,4RS)-1, which is the isomer found in the crystal, is thermodynamically more stable than the diastereomeric (2SR,4RS)-1 by 4.3 ± 0.8 kJ/mol (25°C). In solution, the epimerization by inversion of configuration at the ψ-tetrahedrally coordinated As atom is faster than expected, with acid catalysis (COOH groups!) being a possible cause.
- Von Doellen, Angelika,Strasdeit, Henry
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- Production and use of salts of 6, 8-bis (amidiniumthio) -octanoic acid
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The invention relates to the production and purification of salts of 6,8-bis(amidiniumthio) octanoic acid, its enantiomers (+)-6,8-bis(amidiniumthio)octanoic acid and (-)-6,8-bis (amidiniumthio)octanoic acid and of the esters of these compounds as well as to their use to produce dihydrolipoic acid and α-lipoic acid.
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- Interaction of α-Lipoic acid Enantiomers and Homologues with the Enzyme Components of the Mammalian Pyruvate Dehydrogenase Complex
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Lipoic acid (α-lipoic acid, thioctic acid) is applied as a therapeutic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic acid for the pyruvate dehydrogenase complex and its component enzymes from different sources has been studied. The dihydrolipoamide dehydrogenase component from pig heart has a clear preference for R-lipoic acid, a substrate which reacts 24 times faster than the S-enantiomer. Selectivity is more at the stage of the catalytic reaction than of binding. The Michaelis constants of both enantiomers are comparable (Km = 3.7 and 5.5 mM for R- and S-lipoic acid, respectively) and the S-enantiomer inhibits the R-lipoic acid dependent reaction with an inhibition constant similar to its Michaelis constant. When three lipoic acid homologues were tested, RS-1,2-dithiolane-3-caproic acid was one carbon atom longer than lipoic acid, while RS-bisnorlipoic acid and RS-tetranorlipoic acid were two and four carbon atoms shorter, respectively. All are poor substrates but bind to and inhibit the enzyme with an affinity similar to that of S-lipoic acid. No essential differences with respect to its reaction with lipoic acid enantiomers and homologues exist between free and complex-bound dihydrolipoamide dehydrogenase. Dihydrolipoamide dehydrogenase from human renal carcinoma has a higher Michaelis constant for R-lipoic acid (Km = 18 mM) and does not accept the S-enantiomer as a substrate. Both enantiomers of lipoic acid are inhibitors of the overall reaction of the bovine pyruvate dehydrogenase complex, but stimulate the respective enzyme complexes from rat as well as from Escherichia coli. The S-enantiomer is the stronger inhibitor, the R-enantiomer the better activator. The two enantiomers have no influence on the partial reaction of the bovine pyruvate dehydrogenase component, but do inhibit this enzyme component from rat kidney. The implications of these results are discussed.
- Loeffelhardt, Sabine,Bonaventura, Christoph,Locher, Mathias,Borbe, Harald O.,Bisswanger, Hans
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p. 637 - 646
(2007/10/03)
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- Application of Enzymic Baeyer-Villiger Oxidations of 2-Substituted Cycloalkanones to the Total Synthesis of (R)-(+)-Lipoic Acid
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Oxidation of ketones 1a-h using a monooxygenase from Pseudomonas putida NCIMB 10007 gave the lactones 2a-h in optically active form: lactone 2h was converted into (R)-(+)-lipoic acid 9.
- Adger, Brian,Bes, M. Teresa,Grogan, Gideon,McCague, Ray,Pedragosa-Moreau, Sandrine,et al.
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p. 1563 - 1564
(2007/10/02)
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- Preparation of R/S-γ-lipoic acid or R/S-α-lipoic acid
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A process for preparing R/S-γ-lipoic acid of the formula I or R/S-α-lipoic acid of the formula II STR1 is disclosed.
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- Process for the production of 1,2-dithiolan-3-pentanoic acid (thioctic acid) and intermediate compounds therefor
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1,2-Dithiolane-3-pentanoic acid (D,L-thioctic acid) of the formula STR1 is prepared by a process comprising (a) reacting a 2-(3-alkylthiopropionyl)-cyclopentanone-1 of the formula STR2 where R is a C1 -C4 alkyl, phenyl or benzyl in aqueous alkaline solution at a temperature of about 20° C. to about 90° C. to form the corresponding carboxylic acid of formula VI STR3 (b) reacting the compound of formula VI with an alkyl mercaptan at a temperature between -20° C. and 0° C. to form the corresponding thioketal of formula VII STR4 (c) reacting the compound of formula VII with sodium in liquid ammonia at a temperature between -60° C. and -10° C. to form the 6,8-dimercaptooctanoic acid of formula VIII STR5 (d) reacting the 6,8-dimercaptooctanoic acid of formula VIII in alkaline solution with an iron (III) salt and oxygen to form the 1,2-dithiolane-3-pentanoic acid of formula IX, or in place of steps (a) through (c) reacting an acid of formula XII STR6 where R1 and R2 are hydrogen, C1 -C4 -alkyl, phenyl or benzyl, with the proviso that both R1 and R2 cannot be benzyl, with sodium in liquid ammonia at a temperature between -60° C. and -10° C. to form the corresponding 6,8-dimercaptooctanoic acid of formula VIII. The compounds of formulae VI, VII, XII are new.
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- SYNTHESIS OF 1,3-DIOLS: ITS APPLICATION TO THE SYNTHESIS OF α-LIPOIC ACID
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1,3-diols have been prepared from monosubstitited olefins, and the utility of this method in the synthesis of α-lipoic acid has been described.
- Rao, A. V. Rama,Mysorekar, Sudha V.,Yadav, J. S.
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p. 1339 - 1348
(2007/10/02)
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- One-electron Redox Potentials of RSSR(1+.)-RSSR Couples from Dimethyl Disulphide and Lipoic Acid
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One-electron redox potentials have been measured for three (RSSR)(1+.)/RSSR couples by reference to (SCN)2(1-.)/2 SCN(1-) and/or I2(1-.)/2 I(1-) in pulse radiolysis experiments: E0 (CH3SSCH3(1+.)/CH3SSCH) +(1.391 +/- 0.003) V; E0 COOH(1+.)/lip(SS)COOH> +(1.13 +/- 0.01) V; and E0 COO(1-)(1+.)/lip(SS)COO(1-)> +(1.10 +/- 0.01) V .The paper also includes equilibrium constants for the underlying RSSR + X2(1-.) RSSR(1+.) + 2 X(1-) equilibria (X=SCN or I), and rate constants for the respective back and/or forward reactions.The results are discussed in the light of structural considerations and in relation to other redox couples involving sulphur-centred radial species.
- Bonifacic, Marija,Asmus, Klaus-Dieter
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p. 1805 - 1810
(2007/10/02)
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- Proof that the Absolute Configuration of Natural α-Lipoic Acid is R by the Synthesis of its Enantiomer from (S)-Malic Acid
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The absolute configuration of natural (+)-α-lipoic acid is confirmed to be R by the synthesis of its enantiomer from (S)-malic acid.
- Brookes, Michael H.,Golding, Bernard T.,Howes, David A.,Hudson, Alan T.
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p. 1051 - 1053
(2007/10/02)
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- Oxidation of Dithiols by Flavopapain
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The redox reactions between flavopapain 1 and various dithiols have been examined under anaerobic conditions.The semisynthetic enzyme is an effective catalyst relative to the model flavin, 7-acetyl-10-methylisoalloxazine (3).Relative rate enhancements, (kcat/Km)/k2model, observed are 3.9, 8.0, and 17.4 for dithiotreitol, d,l-dihydrolipoic acid, and d,l-dihydrolipoamide, respectively.This substrate specificity, also seen in N-alkyl-1,4-dihydronicotinamide series, is explicable in terms of favorable hydrophobic-hydrophobic binding interaction between the substrates and the enzyme active site.Stereospecificity was not observed in the enzymatic reactions of the dithiols.It is demonstrated that the enzyme and model flavin reactions of the dithiols both proceeded via comparable mechanistic pathway.
- Fried, Herbert E.,Kaiser, E. T.
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p. 182 - 184
(2007/10/02)
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