ChemInform Abstract: N‐3‐Alkylation of Uracil and Derivatives via N‐1‐Boc Protection.

Jaime‐Figueroa, Saul; Zamilpa, Alejandro; Guzmán, A.; Morgans, David J.

doi:10.1002/chin.200212188

Cited by 3 publications

(3 citation statements)

References 1 publication

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“…The N3-substituted-1-carboxamide derivatives 8a,b, 9a−10a were prepared following a three-step sequence starting from N1-Boc uracils 11a,b (Scheme 2). 17 These compounds were first reacted with the appropriate alkyl iodides in the presence of cesium carbonate to give N3-substituted 2,4-dioxopyrimidine-1-carboxylates. The tert-butyloxycarbonyl group was then removed with potassium carbonate in methanol to afford 3-alkyluracils 12a,b, 13a−14a which were then converted into the corresponding carboxamides 8a,b, 9a−10a following method A. Syntheses of N3-substituted uracils 15a−19a were accomplished with minor modifications of literature procedures, as reported in Scheme 3, by direct N3-acylation of N1-carboxamide derivatives.…”

Section: ■ Chemistrymentioning

confidence: 99%

Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure–Activity Relationship (SAR)

et al. 2013

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Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the first nanomolar inhibitor of intracellular AC activity (rat AC, IC 50 = 0.029 μM). In the present work, we expanded our initial structure−activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimidine-1-carboxamides. Our investigations provided a first elucidation of the structural features of uracil derivatives that are critical for AC inhibition and led us to identify the first single-digit nanomolar inhibitors of this enzyme. The present results confirm that substituted 2,4-dioxopyrimidine-1-carboxamides are a novel class of potent inhibitors of AC. Selected compounds of this class may represent useful probes to further characterize the functional roles of AC.

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Section: ■ Chemistrymentioning

confidence: 99%

Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure–Activity Relationship (SAR)

et al. 2013

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“…This could be advantageous compared with currently utilized strategies, which rely on the initial introduction of protective groups at N1 of thymine or uracil. [43–45] This could be particularly interesting in the context of 3CTAs, which have attracted considerable attention in biomedical research in recent years. [25] All currently available 3CTAs contain a 2′-deoxyribose moiety at N1.…”

Section: Discussionmentioning

confidence: 99%

Iodine Monochloride Facilitated Deglycosylation, Anomerization, and Isomerization of 3-Substituted Thymidine Analogues

Khalil

Ishita

Ali

et al. 2014

Nucleosides, Nucleotides & Nucleic Acids

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The reaction of thymidine, 3-mono-, and 3,3′,5′-trialkylsubstitued thymidine analogues with iodine monochloride (ICl) was investigated. Treatment with ICl resulted in rapid deglycosylation, anomerization, and isomerization of thymidine and 3-substituted thymidine analogues under various reaction conditions leading to the formation of the nucleobases as the major products accompanied by minor formation of α-furanosidic-, α-pyranosidic- and β-pyranosidic nucleosides. On the other hand, 3,3′,5′-trisubstitued thymidine analogues were only deglycosylated and anomerized. These results are similar to those observed for the acidic hydrolysis of the glycoside bond in nucleosides, but were presumably caused by the Lewis acid character of an iodine electrophile.

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“…Tethered compounds 8b–f were prepared by the reaction of N‐(bromoalkyl)‐2,4‐dinitrobenzeneamines 5b–f with 1‐( t ‐butoxycarbonyl)‐5‐fluorouracil 7 in DMF in the presence of sodium hydride followed by removal of 1‐( t ‐butoxycarbonyl) protecting group by potassium carbonate in methanol (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

Synthesis, In Vitro Cytotoxicity and Radiosensitizing Activity of Novel 3‐[(2,4‐Dinitrophenylamino)Alkyl] Derivatives of 5‐Fluorouracil

et al. 2013

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Previously, it was reported that 3[3-(2,4-dinitrophenylamino)-propyl]-5-fluorouracil 8c unlike its components 5-fluorouracil (5-FU) 6 and 2,4-dinitroaniline 2 in HT-29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of 8c differing in the number of linking methylene groups were prepared and tested for in vitro cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound 8a was prepared in one pot by the reaction of 5-FU 6 with paraformaldehyde and 2,4-dinitroaniline 2 in the presence of the concentrated hydrochloric acid, and compounds 8b-f were prepared by the reaction of N-(bromoalkyl)-2,4-dinitrobenzeneamines 5b-f with 1-(t-butoxycarbonyl)-5-fluorouracil 7 followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and propidium iodide (PI)-digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds 8a-f induced time- and concentration-dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration-dependent radiocytotoxicity under hypoxic conditions.

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ChemInform Abstract: N‐3‐Alkylation of Uracil and Derivatives via N‐1‐Boc Protection.

Cited by 3 publications

References 1 publication

Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure–Activity Relationship (SAR)

Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure–Activity Relationship (SAR)

Iodine Monochloride Facilitated Deglycosylation, Anomerization, and Isomerization of 3-Substituted Thymidine Analogues

Synthesis, In Vitro Cytotoxicity and Radiosensitizing Activity of Novel 3‐[(2,4‐Dinitrophenylamino)Alkyl] Derivatives of 5‐Fluorouracil

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