An Improved Synthesis of Willardiine and 1-(2',2'-Diethoxyethyl)uracil<sup>1</sup>

Martinez, Abelardo P.; Lee, William W.

doi:10.1021/jo01012a521

Cited by 46 publications

(8 citation statements)

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“…Miscellaneous Compounds. dl -Willardiine ( 7 ) was synthesized by the method of Martinez and Lee we readily repeated their procedure for the nitration of willardiine.…”

Section: Methodsmentioning

confidence: 99%

Structure−Activity Studies for α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid Receptors: Acidic Hydroxyphenylalanines

et al. 1997

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Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors may have therapeutic potential as psychotropic agents. A series of mononitro- and dinitro-2- and 3-hydroxyphenylalanines was prepared, and their activity compared with willardiine, 5-nitrowillardiine, AMPA, and 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) as inhibitors of specific [3H]AMPA and [3H]kainate binding in rat brain homogenates. The most active compounds were highly acidic (pKa 3-4), namely, 2-hydroxy-3,5-dinitro-DL-phenylalanine (13; [3H]AMPA IC50 approximately equal to 25 microM) and 3-hydroxy-2,4-dinitro-DL-phenylalanine (19; [3H]AMPA IC50 approximately equal to 5 microM). Two other dinitro-3-hydroxyphenylalanines, and 3,5-dinitro-DL-tyrosine, were considerably less active. Various mononitrohydroxyphenylalanines, which are less acidic, were also less active or inactive, and 2- and 3-hydroxyphenylalanine (o- and m-tyrosine) were inactive. Compounds 13 and 19, DL-willardiine (pKa 9.3, [3H]AMPA IC50 = 2 microM), and 5-nitro-DL-willardiine (pKa 6.4, [3H]AMPA IC50 = 0.2 microM) displayed AMPA >> kainate selectivity in binding studies. Compound 19 was an AMPA-like agonist, but 13 was an antagonist in an AMPA-evoked norepinephrine release assay in rat hippocampal nerve endings. Also, compound 13 injected into the rat ventral pallidum antagonized the locomotor activity elicited by systemic amphetamine.

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“…Miscellaneous Compounds. dl -Willardiine ( 7 ) was synthesized by the method of Martinez and Lee we readily repeated their procedure for the nitration of willardiine.…”

Section: Methodsmentioning

confidence: 99%

Structure−Activity Studies for α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid Receptors: Acidic Hydroxyphenylalanines

et al. 1997

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“…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. We have attempted the synthesis of a range of 5-halo-substituted 1-(formylmethyl)pyrimidine-2,4-diones using the procedures previously described for the synthesis of the unsubstituted aldehyde 16,17 but obtained only poor yields of impure aldehydes.…”

Section: Chemistrymentioning

confidence: 99%

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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“…Alternatively, the bases were first converted into 2-substituted acetaldehyde acetals, capable of forming 1,3-dioxane rings by transacetal formation with the 1,3-diol moieties in PVA, as described in the earlier literature [ 32 ]. Thus, uracil ( 2 ) was reacted with 2-bromo-1,1-diethoxyethane ( 4 ) in the presence of NaH in DMF to afford the 1-(2’,2’-diethoxyethyl)-uracil 5 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Polynucleotide Analogs Containing a Polyvinyl Alcohol Backbone

Carlsen

2008

Molecules

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Water soluble homo-base polynucleotide analogues were synthesized in which polyvinyl alcohol and partially phosphonated polyvinyl alcohol constituted the backbones, onto which were grafted uracil or adenine via 1,3-dioxane spacers formed by acetal formation with the 1,3-diol moieties in PVA. The resulting adenine-PVA polynucleotide analogs exhibited hyperchromic effects, which was not the case for the corresponding uracil compounds. Mixtures of the adenine- and aracil PVA-phosphate polynucleotide analogs in solutions exhibited characteristic S-shaped UV-absorbance vs temperature and melting curves with melting points at approximately 40 oC.

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An Improved Synthesis of Willardiine and 1-(2',2'-Diethoxyethyl)uracil¹

Cited by 46 publications

References 1 publication

Structure−Activity Studies for α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid Receptors: Acidic Hydroxyphenylalanines

Structure−Activity Studies for α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid Receptors: Acidic Hydroxyphenylalanines

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

Synthesis of Polynucleotide Analogs Containing a Polyvinyl Alcohol Backbone

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An Improved Synthesis of Willardiine and 1-(2',2'-Diethoxyethyl)uracil1

Cited by 46 publications

References 1 publication

Structure−Activity Studies for α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid Receptors: Acidic Hydroxyphenylalanines

Structure−Activity Studies for α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid Receptors: Acidic Hydroxyphenylalanines

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

Synthesis of Polynucleotide Analogs Containing a Polyvinyl Alcohol Backbone

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An Improved Synthesis of Willardiine and 1-(2',2'-Diethoxyethyl)uracil¹