Aromatic amino acid hydroxylase inhibitors. 2. 3-Alkyl-.alpha.-methyltyrosines

Counsell, Raymond E.; Desai, Pritesh R.; Ide, Akio; Kulkarni, P. G.; Weinhold, Paul A.; Rethy, V. B.

doi:10.1021/jm00291a003

Cited by 8 publications

(5 citation statements)

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“…The benzyl group was introduced by reaction with 2,4-di-tert-butyl-2-hydroxy benzaldehyde in the presence of potassium carbonate using DMF to give 3 as the product. A similar type of reaction has been reported by Counsell and co-workers in the synthesis of di-substituted 1-phenol-2-propanones, 56 and by Belmar and Jiménez for preparing hindered polyanionic chelating ligands. 57 Crystals of 3 were grown from hexane by evaporation; the structure elucidated is shown in Figure 3.…”

Section: Pendent Arm Synthesissupporting

confidence: 63%

Side-bridged cyclam transition metal complexes bearing a phenolic ether or a phenolate pendent arm

Mewis

Archibald

2019

Polyhedron

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Side-bridged cyclam transition metal complexes (M = Ni(II), Cu(II) and Zn(II)) bearing a phenolic ether or phenolate pendent arm have been synthesised. For [NiL 1 ] + and [CuL 1 ] + , evidence for a phenoxyl radical was obtained (quasi reversible peak at +0.74 V and +0.48 V respectively), as well as oxidation of OH, due to protonation of the phenolate, at ~+1.24 V. The phenoxyl radical in [Ni(L 1 )] 2+ is harder to oxidise by 0.26 V compared with the corresponding Cu(II) complex. UV-Vis data for [Ni(L 1 )] 2+ suggests that the Ni(II) ion may be 4 or 6 coordinate whereas the Cu(II) ion in [Cu(L 1 )] 2+ is five coordinate. The Ni(II) ion in the crystal structure of [Ni( L 2 )][( ClO4)2] possesses a distorted squareplanar geometry in which the phenolic ether pendent arm is not involved in the coordination sphere. The cyclam ligand in this complex adopts a trans-II configuration.

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Section: Pendent Arm Synthesissupporting

confidence: 63%

Side-bridged cyclam transition metal complexes bearing a phenolic ether or a phenolate pendent arm

Mewis

Archibald

2019

Polyhedron

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“…Also shown is the 2-hiscarboxylate triad anchoring the active site iron. of Udenfriend [122][123][124][125], Counsell [42,[126][127][128] and others was that the inhibition of TH, catalyzing the rate-limiting step in norepinephrine biosynthesis, would lead to a decrease in vascular tone and thus function as an antihypertensive therapy. Halogenated derivatives of phenylalanine were discovered to be potent inhibitors of both TH and PAH in vitro, with preferential inhibition of TH by the metahalogenated compounds [126].…”

Section: The Iron Sitementioning

confidence: 99%

“…The halogenated analogs lack significant in vivo activity because they are rapidly destroyed by dehalogenases and transaminases [129]. Several compounds with alkyl groups attached to the meta position of the ring in α-methyltyrosine were also synthesized and found to inhibit TH [42,46]. The strong affinity for the chloro-probe in the vicinity of the metaposition of L-Tyr indicated that this area has a strong affinity for halogens and explains the preferential inhibition of TH for these compounds (Fig.…”

Section: The Iron Sitementioning

confidence: 99%

“…In contrast, inhibitors of PAH were designed as experimental tools to generate animal models or cell lines suitable to studies on PKU [41]. At a remarkable speed, a range of amino acid substrate analogs of the AAHs was synthesized and tested therapeutically [3,[42][43][44]. Particularly for TH, it was soon shown that tyrosine derivatives with bulky substituents in the meta-position act as potent competitive inhibitors (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Selectivity and Affinity Determinants for Ligand Binding to the Aromatic Amino Acid Hydroxylases

Teigen

McKinney²,

Haavik³

et al. 2007

CMC

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Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin (BH4) dependent enzymes, i.e. the aromatic amino acid hydroxylases (AAHs). The reactions catalyzed by these enzymes are important for biomedicine and their mutant forms in humans are associated with phenylketonuria (phenylalanine hydroxylase), Parkinson's disease and DOPA-responsive dystonia (tyrosine hydroxylase), and possibly neuropsychiatric and gastrointestinal disorders (tryptophan hydroxylase 1 and 2). We attempt to rationalize current knowledge about substrate and inhibitor specificity based on the three-dimensional structures of the enzymes and their complexes with substrates, cofactors and inhibitors. In addition, further insights on the selectivity and affinity determinants for ligand binding in the AAHs were obtained from molecular interaction field (MIF) analysis. We applied this computational structural approach to a rational analysis of structural differences at the active sites of the enzymes, a strategy that can help in the design of novel selective ligands for each AAH.

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“…Syntheses of these hydrazides have been described previously. 7 Pharmacological Results. Acute Toxicity.…”

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confidence: 99%

Aromatic amino acid hydroxylase inhibitors. 4. 3-Substituted .alpha.-methyltyrosines

El-Masry¹,

el-Masry²,

Hare³

et al. 1975

J. Med. Chem.

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In the present study a series of 3-alkenyl-alpha-methyltyrosines and their corresponding 3-alkyl-and dihydrobenzofuran analogs was synthesized for potential tyrosine hydroxylase (TH) inhibitory activity. The appropriately substituted hydantoins IIIa and IIIb, which were prepared from the corresponding allyloxybenzylhydantoins IIa and IIb through Claisen rearrangement, served as intermediates for the synthesis of these amino acids. TH inhibition was reduced upon either saturation of the double bond in the side chain or cyclization to form the dihydrobenzofuran analogs. Formation of the epoxide had a similar effect. The inhibitory activity of these compounds against aromatic amino acid decarboxylase (AADC) and dopamine beta-hydroxylase (DBH) was also investigated. Unsaturation, in both cases, decreases the inhibitory activity; however, the presence of a free phenolic group appears to be essential for AACD inhibitory activity.

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Aromatic amino acid hydroxylase inhibitors. 2. 3-Alkyl-.alpha.-methyltyrosines

Cited by 8 publications

References 0 publications

Side-bridged cyclam transition metal complexes bearing a phenolic ether or a phenolate pendent arm

Side-bridged cyclam transition metal complexes bearing a phenolic ether or a phenolate pendent arm

Selectivity and Affinity Determinants for Ligand Binding to the Aromatic Amino Acid Hydroxylases

Aromatic amino acid hydroxylase inhibitors. 4. 3-Substituted .alpha.-methyltyrosines

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