110. Purines, pyrimidines, and imidazoles. Part XVII. A synthesis of willardiine

Dewar, John; Shaw, G.

doi:10.1039/jr9620000583

Cited by 32 publications

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“…( S ) - 1 -(2-Amino-2-carboxyethy l )pyrimidine-2,4-dione ( 1 8) was obtained similarly from pyrimidine-2,4-dione ( 7 ) (5.39 g, 48.1 mmol), a 60% suspension of sodium hydride in mineral oil (1.8 g, 48 mmol) in dry DMF (100 mL), and ( S )-3-[( tert -butoxycarbonyl)amino]oxetan-2-one ( 17 ) (3.00 g, 16.1 mmol). Deprotection in TFA (40 mL) followed by purification by ion-exchange chromatography and crystallization from water as described for 24 gave ( S )-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione ( 18 ) (2.24 g, 63%) as a white solid: mp 207−208 °C dec (lit . mp 206−211 °C); [α] 25 D −24.4° ( c 1.16, 6 M HCl) (lit .…”

Section: Methodsmentioning

confidence: 99%

“…Deprotection in TFA (40 mL) followed by purification by ion-exchange chromatography and crystallization from water as described for 24 gave ( S )-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione ( 18 ) (2.24 g, 63%) as a white solid: mp 207−208 °C dec (lit . mp 206−211 °C); [α] 25 D −24.4° ( c 1.16, 6 M HCl) (lit . [α] 20 D −20° ( c 2.0, 1 M HCl)); 1 H NMR (300.4 MHz, DCl/D 2 O, pH 1) δ 4.33−4.54 (ABX system, 2H, J = 15.4, 4.5, 6.5 Hz), 4.61 (dd, 1H, J = 4.6, 4.6 Hz), 5.88 (d, 1H, J = 7.9 Hz), 7.70 (d, 1H, J = 7.9 Hz); 13 C NMR (300.4 MHz, DCl/D 2 O, pH 1) δ 50.5, 54.6, 104.6, 149.4, 155.3, 168.8, 171.0.…”

Section: Methodsmentioning

confidence: 99%

“…(S)-3-[(tert-Butoxycarbonyl)amino]-oxetan-2-one (17) was synthesized by the reported procedure. 18,19 The 6-azauracils (14,15) were synthesized using a literature method. 24 All other reagents were obtained from Aldrich Chemical Co. All uracils (7)(8)(9)(10)(11)(12)(13)(14)(15)(16) were dried in vacuo (0.1 mmHg) over P2O5 for 3 days before use.…”

Section: Methodsmentioning

confidence: 99%

“…Racemic willardiine ( 6 ) has been previously synthesized in a 62% yield utilizing the Strecker amino acid synthesis with 1-(formylmethyl)pyrimidine-2,4-dione as the substrate . Yields in the first two stages involving the synthesis of 1-(formylmethyl)pyrimidine-2,4-dione have been improved. − However, this approach to the synthesis of willardiines has a number of disadvantages: it involves a multistep synthesis, cannot be applied to a range of substituted analogs, and leads to racemic mixtures, which require resolution in order to obtain the individual enantiomers.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis of Willardiine and 6-Azawillardiine Analogs: Pharmacological Characterization on Cloned Homomeric Human AMPA and Kainate Receptor Subtypes

et al. 1997

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Both willardiine and azawillardiine analogs (18-28) have been reported to be potent and selective agonists for either AMPA or kainate receptors. We report here the novel synthesis and pharmacological characterization of a range of willardiine (18-23) and 6-azawillardiine (24-28) analogs on cells individually expressing human homomeric hGluR1, hGluR2, hGluR4, or hGluR5 receptors. Reaction of the sodium salts of substituted uracils (7-12) or 6-azauracils (13-16) with (S)-3-[(tert-butoxycarbonyl)amino]oxetan-2-one (17) in dry DMF, subsequent deprotection in TFA, and purification by ion-exchange chromatography gave mainly the willardiine analog in which alkylation took place on N1 of the uracil ring. We have investigated the subtype selectivity of these compounds by examining their binding affinity for homomeric hGluR1, -2, -4, or -5 (and hGluR6 in the case of 5-iodowillardiine (22)). From this study we have demonstrated that 22 has high affinity for hGluR5 and, compared to kainate, displays excellent selectivity for this receptor over both the AMPA receptor subtypes and the homomeric kainate receptor, hGluR6. 5-Fluorowillardiine (19) has higher affinity than AMPA for both homomeric hGluR1 and hGluR2 and compared to AMPA displays greater selectivity for AMPA receptor subtypes over the kainate receptor, hGluR5. Some structural features required for optimal activity at homomeric AMPA or kainate receptor subtypes have also been identified. It would appear that quite large lipophilic substituents at the 5-position of the uracil ring not only are accommodated by hGluR5 receptors but also lead to enhanced affinity for these receptors. In contrast to this, for optimal binding affinity to hGluR1, -2, or -4, smaller, electron-withdrawing substituents are required. For optimal activity at hGluR4 receptors a 6-aza-substituted willardiine is favored. The subtype-selective compounds described here are likely to be useful tools to probe the distribution and the physiological roles of the various glutamate receptor subunits in the central nervous system.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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Synthesis of Willardiine and 6-Azawillardiine Analogs: Pharmacological Characterization on Cloned Homomeric Human AMPA and Kainate Receptor Subtypes

et al. 1997

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“…It was later reported to occur in other species of Acacia and in Mimosa asperata (Gmelin, 1961). Structurally, willardiine (I) is #-(2,4-dihydroxypyrimidin-1-yl)alanine (Gmelin, 1959); identification was confirmed by synthesis by Kjaer et al (1961), Shaw & Dewar (1961) and Dewar & Shaw (1962). The occurrence of a second uracilylalanine was recognized by Brown & Silver (1966), who isolated it from pea seedlings and tentatively identified it as fl-(2,4-dihydroxypyrimidin-5-yl)alanine.…”

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confidence: 98%

Biosynthesis of willardiine and isowillardiine in germinating pea seeds and seedlings

Ashworth

Brown

Roberts

1972

Biochemical Journal

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The synthesis of the pyrimidinyl amino acids willardiine and isowillardiine was studied in vivo and in vitro. Uracil derivatives stimulate the biosynthesis of both compounds; the free base is the most effective. Significant incorporation of [2-(14)C]uracil and [6-(14)C]orotate into willardiine and isowillardiine was found. Incorporation of [6-(14)C]orotate was substantially decreased in the presence of uracil, and to a lesser extent by uridine and UMP. [3-(14)C]Serine was incorporated into the alanine side chain of the two uracilylalanines but not into the ring. The effect of a number of uracil analogues and inhibitors of pyrimidine metabolism was examined. Some were shown to stimulate the biosynthesis; the most noticeable effects were obtained with 6-azauracil and 2-thiouracil. Attempts to obtain extracts capable of synthesizing the uracilylalanines from uracil and serine were unsuccessful, but weak activity was observed when serine was replaced by O-acetylserine.

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References

1970

Chemistry of Heterocyclic Compounds: A Series of Monographs

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110. Purines, pyrimidines, and imidazoles. Part XVII. A synthesis of willardiine

Cited by 32 publications

References 0 publications

Synthesis of Willardiine and 6-Azawillardiine Analogs: Pharmacological Characterization on Cloned Homomeric Human AMPA and Kainate Receptor Subtypes

Synthesis of Willardiine and 6-Azawillardiine Analogs: Pharmacological Characterization on Cloned Homomeric Human AMPA and Kainate Receptor Subtypes

Biosynthesis of willardiine and isowillardiine in germinating pea seeds and seedlings

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