L-3, 4-Dihydroxyphenylalanine

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

The nigrostriatal system is predominantly involved in motor control, which is particularly evident in Parkinson s disease (PD), where a progressive loss of these neurons results in loss of motor function. In the early stages of the disorder, the motor impairment can be reversed by the administration of the dopamine precursor l-DOPA (L-3,4-dihydroxyphenylalanine), which bypasses the need for TH in dopamine... 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

Fio. 51. Dependence of retention of catecholamines on volume percent acetonitrile in hetaeric chromatography. The ehient is water-acetonitrile at the volume percent indicated containing 0.2% (v/v) sulfuric acid and 0.1% (w/v) sodium dodecyl sulfote. The catecholamines separated are noradrenaline (NA), adrenaline (A). L-3,4-dihydroxyphenylalanine (LD), normetanephrine (NMA), dopamine (DA), metadrenaline (MA), and 3-methoxytyramine (MDA). Column 5- tm octadecyl silica treated with triroethylchlorosilane, 125 X 5 mm i.d. Reprinted with permission from Knox and Jurand (223). ... 

Uses. The main application of vanillin is the flavoring of foods (e.g., ice cream, chocolate, bakery products, and confectioneries). Small quantities are used in perfumery to round and fix sweet, balsamic fragrances. Vanillin is also used as a brightener in galvanotechnical processes and is an important intermediate in, for example, the production of pharmaceuticals such as L-3,4-dihydroxyphenylalanine (l-DOPA) and methyldopa. 

A particularly well-studied ligand is L-3,4-dihydroxyphenylalanine (l-DOPA) this may coordinate like alaninate or a pyrocatechol 700 Zn11 appears to favour binding to l-DOPA as to pyrocatechols.701 Formation constants have been measured for the ternary complexes Zn11 dopamine alanine/pyrocatechol702 and Zn11 l-DOPA L (L = penicillamine, L-alanine, glycine, 2,2 -bipyridine, citric add, tartaric acid or sulfosalicylic add). 3... 

Fujii, Y., Shibuya, T., Yasuda, T. L-3,4-Dihydroxyphenylalanine as an allelochemical candidate fromMucuna puriens (L.) DC. var. utilis. Agricult Biolog Chem 1991 55 617-618. 

One of the first mentions of an imprinted sol-gel-derived silica thin film that was able to discriminate against enantiomers was that of Marx and Liron, who created a chiral cavity for propranolol.66 In a note added to the proof, the authors reported on data that showed a cavity templated with the pure enantiomer, 5-propranolol, that discriminated between it and the R-enantiomer.66 In a later publication, more details were provided on this method and two additional systems (R)- and (5)-2,2,2-trifluoro-1 -(9-anthryl) ethanol and d- and L-3,4-dihydroxyphenylalanine.67... 

Tyrosinase inhibitors prevent browning in foodbecause they inhibit the oxidation caused by the enzyme tyrosinase. Cuminaldehyde is identified as a potent mushroom tyrosinase monophenol monooxygenase inhibitor from cumin seeds, ft inhibits the oxidation of L-3,4-dihydroxyphenylalanine (l-DOPA) by mushroom tyrosinase with an ID50 of 7.7g/ml (0.05 mM). Its oxidized analogue, cumic acid (p-isopropylbenzoic acid), also inhibits this oxidation with an 1D50 of 43g/ml (0.26mM). These two inhibitors affect mushroom tyrosinase activity in different ways (Kubo and Kinst-Hori, 1998). 

An asymmetric synthesis of ( —)-(i )-Iaudanosine has been accomplished, proceeding from L-3,4-dihydroxyphenylalanine via the norlaudanosine derivatives (18 R1 = H, R2 = C02Me), (18 R1 = CH2Ph, R2 = CONH2), and (18 R1 = CH2Ph, R2 = CN), which was then converted into norlaudanosine (18 R1 = R2 = H). The nor-base was then jV-formylated and the N-formyl derivative reduced with sodium borohydride. The C-l epimer of the ester (18 R1 = H, R2 = C02Me) was also obtained, and it isomerized to the trans-ester when mixed with sodium methoxide in methanol.28... 

Decarboxylation of L-3,4-dihydroxyphenylalanine to dopamine, and of 5-hydroxytryptophan to serotonin, is catalyzed by aromatic L-amino acid decarboxylase. A single enzyme may be responsible for both activities. This assay permits simultaneous determination of both activities. 

Proof of enantiomeric purity is necessary in the case of L-3,4-dihydroxyphenylalanine (L-DOPA), a drug used to treat Parkinson s disease, because of the high toxidty of the D enantiomer. Previously, D,L-DOPA was resolved by Frank, Nicholson, and Bayer using Chirasil-val (41). Figure 6 shows the separation of D, L-DOPA on a column with per-pentylated ot-cydodextrin. In the case of a-methyl-DOPA (Aldomet) [4], a drug that is used in its L form for its antihypertensive activity, the enan-... 

Thus, peroxidase is capable of catalyzing the synthesis of three important drugs, L-3,4-dihydroxyphenylalanine (XII) (Scheme VII), d-(-)-3,4-dihydroxyphenylglycine and L-epinephrine with yields up to 70 % [90]. 

A further industrially important lyase for the production of L-amino acids is the tyrosine phenol lyase [39]. This biocatalyst is used by Ajinomoto in the production of the pharmaceutically important L-3,4-dihydroxyphenylalanine (L-dopa), 32, which is applied in the treatment of Parkinson s disease. The reaction concept is based on a one-pot three-component synthesis starting from catechol, 30, pyruvic acid, 31, and ammonia in the presence of suspended whole cells (strain Erwinia herbicola) containing the tyrosine phenol lyase biocatalyst (Fig. 16). A key feature of this process is the high volumetric productivity of 110 g/L of the desired L-dopa product. Notably, this reaction runs with an annual capacity of 250 tons. 

In this particular problem, a set of 27 samples containing different amounts of L-phenylalanine, L-3,4-dihydroxyphenylalanine (DOPA), 1,4-dihydroxybenzene and L-tryptophan have been measured by fluorescence spectroscopy [Baunsgaard 1999, Riu Bro 2002], The data are important as a model system for many biological systems, e.g. in food and environmental analysis. The goal here is to develop a PARAFAC model of the measured data because a PARAFAC model will ideally resolve the pure spectra as well as the relative concentrations of the analytes [Bro 1997, Bro 1998, Bro 1999, Leurgans et al. 1993, Leurgans Ross 1992, Ross Leurgans 1995]. 

The product is applied for the treatment of Parkinsonism that is caused by a lack of l-dopamine and its receptors in the brain. L-Dopamine is synthesized in organisms by decarboxylation of L-3,4-dihydroxyphenylalanine (L-dopa). Since L-dopamine cannot pass the blood-brain barrier L-dopa is applied in combination with dopadecarbox-ylase-inhibitors to avoid formation of L-dopamine outside the brain. Ajinomoto produces L-dopa by this lyase-biotransformation with suspended whole cells in a fed batch reactor on a scale of 250 t a-1. Much earlier, Monsanto has successfully scaled up the chemical synthesis of L-dopa (Fig. 19-38). 

DDC catalyzes the conversion of L-3,4-dihydroxyphenylalanine (l-DOPA) into dopamine (Figure 10), a neurotransmitter found in the nervous system and peripheral tissues of both vertebrates and invertebrates and also in plants where it is implicated in the biosynthesis of benzylisoquinoline alkaloids. " DDC also catalyzes the decarboxylation of tryptophan, phenylalanine, and tyrosine and of 5-hydroxy-L-tryptophan to give 5-hydroxytryptamine (serotonin), and, therefore, is also referred to as aromatic amino acid decarboxylase. Inhibitors of DDC, for example, carbiDOPA and benserazide, are currently used in the treatment of Parkinson s disease to increase the amount of l-DOPA in the brain. 

The classic example of this approach involves the use of levodopa (l-3,4-dihydroxyphenylalanine, Figure 8.13) to treat Parkinson s disease [58]. Parkinson s disease is distinguished by the marked depletion of dopamine— an essential neurotransmitter—in the basal ganglia. Direct dopamine replacement is not possible, because dopamine does not permeate through the blood-brain barrier. However, the metabolic precursor of dopamine, levodopa, is transported across brain capillaries by the neutral amino acid transporter (see Table 5.5 and the related discussion). Peripheral administration of levodopa, therefore, produces an increase in levodopa concentration within the central nervous system some of these molecules are converted into dopamine due to the presence of decarboxylate enzymes in the brain tissue, but decar-boxylate activity is also present in the intestines and blood. To prevent conversion of levodopa into dopamine before entry to the brain, levodopa is usually administered with decarboxylase inhibitors. 

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