- Discovery of a new class of highly potent inhibitors of acid ceramidase: Synthesis and structure-activity relationship (SAR)
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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, IC50 = 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.
- Pizzirani, Daniela,Pagliuca, Chiara,Realini, Natalia,Branduardi, Davide,Bottegoni, Giovanni,Mor, Marco,Bertozzi, Fabio,Scarpelli, Rita,Piomelli, Daniele,Bandiera, Tiziano
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p. 3518 - 3530
(2013/06/27)
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- The photocycloaddition reactions of uridine and related compounds with 2,3-dimethyl-2-butene
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The photochemical reactions of uracil and 5-fluorouracil derivatives with simple alkenes have been investigated. Photocycloaddition of uracil or 5-fluorouracil derivatives and 2,3-dimethyl-2-butene in acetone gave an enantiomeric mixture of cross cycloadducts (4, 7) in moderate yields. Under similar conditions, diastereomers of 4-substituted 7,7,8,8-tetramethyl-cis-2,4-diazabicyclo[4.2.0]octane-3,5-dione nucleosides (14-17) were formed from uridine or 5-fluorouridine derivatives in good yields. The structures and stereochemistry of these cycloadducts of the nucleoside series were elucidated on the basis of the proton nuclear magnetic resonance spectra and X-ray crystallographic analysis.
- Ishikawa,Itoh,Takayanagi,Oshima,Kawahara,Mizuno,Ogura
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p. 1922 - 1930
(2007/10/02)
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- New tetramethyl-cis-diaza-bicyclo{4.2.0}octane-3,5-dione derivatives having differentiation-inducing activity and antiviral activity
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As new compounds are now provided 7,7,8,8,-tetramethyl-cis-diaza-bicyclo{4.2.0}octane-3,5,-dione derivatives which have an activity to induce the differentiation of tumor cells and are useful as antitumor agent, and which also have an antiviral activity against various viruses and are useful as antiviral agent. These new derivatives may be produced by a photo-addition reaction of a uracil compound with 2,3-dimethyl-2-butene.
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- Glorination of Pyrimidines. Part 2. Mechanistic Aspects of the Reaction of Acetyl Hypofluorite with Uracil and Cytosine Derivatives
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The reaction of acetyl hypofluorite (AcOF) with uracil, cytosine, and some N-1-substituted derivatives dissolved in either acetic acid or water has been investigated.Analysis by radio-h.p.l.c., using (18)f as a tracer, and by (1)H n.m.r. revealed that a substituent at N-1 of uracil has a remarkable effect on the stability of the intermediate 6-acetoxy-5-fluoro-5,6-dihydrouracils.In addition, it was found that these cytosine adducts rapidly deaminate in water yielding their corresponding uracil analogues.
- Visser, W. M. Gerard,Herder, E. Renella,Kanter, Frans J. J. de,Herscheid D. M. Jacobus
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p. 1203 - 1208
(2007/10/02)
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- Application of the Benzyloxycarbonyloxymethyl Moiety to a Protective Group of 5-Fluoroacil. Selective Alkylation of Amide Nitrogen of the Uracil Ring
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Selective alkylation of 5-fluorouracil using the benzoyloxycarbonyloxymethyl moiety as a protective group of amide nitrogen of the uracil ring is described.Protection, alkylation and deprotection were carried out in high yields.
- Nagase, Toshio,Seike, Kanzo,Shiraishi, Kazuto,Yamada, Yutaka,Ozaki, Shoichiro
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p. 1381 - 1384
(2007/10/02)
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- A NOVEL ROUTE TO 5-FLUOROURACILS FROM CHLOROTRIFLUOROETHENE
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Diethyl fluoromalonate was prepared in one-pot from chlorotrifluoroethene via trifluoroacrylic acid lithium salt in 79percent yield.Diethyl fluoromalonate was easily converted to 5-fluoro-6-chlorouracils, reductions of which gave 5-fluorouracils in good yields.
- Fuchikami, Takamasa,Yamanouchi, Akiko,Suzuki, Yasuyuki
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p. 1573 - 1576
(2007/10/02)
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