- Structure-activity relationships of orotidine-5′-monophosphate decarboxylase inhibitors as anticancer agents
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A series of 6-substituted and 5-fluoro-6-substituted uridine derivatives were synthesized and evaluated for their potential as anticancer agents. The designed molecules were synthesized from either fully protected uridine or the corresponding 5-fluorourid
- Bello, Angelica M.,Konforte, Danijela,Poduch, Ewa,Furlonger, Caren,Wei, Lianhu,Liu, Yan,Lewis, Melissa,Pai, Emil F.,Paige, Christopher J.,Kotra, Lakshmi P.
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- Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides
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A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P–N bond cleavage and free nucleoside 5′-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.
- Slusarczyk, Magdalena,Ferla, Salvatore,Brancale, Andrea,McGuigan, Christopher
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- Nucleolipids of the cancerostatic 5-fluorouridine: Synthesis, adherence to oligonucleotides, and incorporation in artificial lipid bilayers
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5-Fluorouridine (1a) was converted to its N(3)-farnesylated nucleoterpene derivative 8 by direct alkylation with farnesyl bromide (4). Reaction of the cancerostatic 1a with either acetone, heptan-4-one, nonadecan-10-one, or hentriacontan-16-one afforded the 2',3'-O-ketals 2a-2d. Compound 2b was then first farnesylated (→5) and subsequently phosphitylated to give the phosphoramidite 6. The ketal 2c was directly 5'-phosphitylated without farnesylation of the base to give the phosphoramidite 7. Moreover, the recently prepared cyclic 2',3'-O-ketal 11 was 5'-phosphitylated to yield the phosphoramidite 12. The 2',3'- O-isopropylidene derivative 2a proved to be too labile to be converted to a phosphoramidite. All novel derivatives of 1a were unequivocally characterized by NMR and UV spectroscopy and ESI mass spectrometry, as well as by elemental analyses. The lipophilicity of the phosphoramidite precursors were characterized by both their retention times in RP-18 HPLC and by calculated log P values. The phosphoramidites 6, 7, and 12 were exemplarily used for the preparation of four terminally lipophilized oligodeoxynucleotides carrying a cyanine-3 or a cyanine-5 residue at the 5'-(n-1) position (i.e., 14-17). Their incorporation in an artificial lipid bilayer was studied by single-molecule fluorescence spectroscopy and fluorescence microscopy.
- Malecki, Edith,Ottenhaus, Vanessa,Werz, Emma,Knies, Christine,Martinez, Malayko Montilla,Rosemeyer, Helmut
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- CANCER THERAPY WITH MICROBUBBLES.
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The invention relates to a microbubble-chemotherapeutic agent complex comprising a microbubble carrying a combination of chemotherapeutic agents for use in a method of treating cancer in a patient, wherein said combination of chemotherapeutic agents comprises: (a) a 5-fluoropyrimidine or a derivative thereof; (b) irinotecan or a derivative thereof; and (c) a platinum-based chemotherapeutic agent or a derivative thereof; and wherein said method comprises simultaneous, separate or sequential administration of folinic acid or a derivative thereof. The invention is particularly suitable for use in the treatment of deep-sited tumours and associated metastatic disease, for example in the treatment of pancreatic cancer. The invention further relates to the microbubble- chemotherapeutic agent complexes themselves, to methods for their preparation and to pharmaceutical compositions which contain them, optionally in combination with folinic acid or a folinic acid derivative.
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Page/Page column 24
(2021/10/11)
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- Unified Total Synthesis of Polyoxins J, L, and Fluorinated Analogues on the Basis of Decarbonylative Radical Coupling Reactions
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Polyoxins J (1 a) and L (1 b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1 a and 1 b contain thymine and uracil nucleobases, respectively. Herein we report the unified total synthesis of 1 a, 1 b, and their artificial analogues 1 c and 1 d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between α-alkoxyacyl tellurides and a chiral glyoxylic oxime ether led to chemo- and stereoselective construction of the ribonucleoside α-amino acid structures of 1 a–d without damaging the preinstalled nucleobases. The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1 a–d. The two amino acid fragments were connected and elaborated into 1 a–d (longest linear sequence: 11 steps). Compounds 1 a and 1 b assembled in this way exhibited potent activity against true fungi, while only 1 d was active against Gram-positive bacteria.
- Fujino, Haruka,Nagatomo, Masanori,Paudel, Atmika,Panthee, Suresh,Hamamoto, Hiroshi,Sekimizu, Kazuhisa,Inoue, Masayuki
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supporting information
p. 11865 - 11869
(2017/09/20)
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- Synthesis and structure-activity relationship of uracil nucleotide derivatives towards the identification of human P2Y6 receptor antagonists
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P2Y6 receptor (P2Y6-R) is involved in various physiological and pathophysiological events. With a view to set rules for the design of UDP-based reversible P2Y6-R antagonists as potential drugs, we established structure-activity relationship of UDP analogues, bearing modifications at the uracil ring, ribose moiety, and the phosphate chain. For instance, C5-phenyl- or 3-NMe-uridine-5′-α,β-methylene-diphosphonate, 16 and 23, or lack of 2′-OH, in 12-15, resulted in loss of both agonist and antagonist activity toward hP2Y6-R. However, uridylyl phosphosulfate, 19, selectively inhibited hP2Y6-R (IC50 112 μM) versus P2Y2/4-Rs. In summary, we have established a comprehensive SAR for hP2Y6-R ligands towards the development of hP2Y6-R antagonists.
- Meltzer, Diana,Ethan, Ophir,Arguin, Guillaume,Nadel, Yael,Danino, Ortal,Lecka, Joanna,Sévigny, Jean,Gendron, Fernand-Pierre,Fischer, Bilha
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p. 5764 - 5773
(2015/11/11)
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- 5-Fluoruoracil Derivatives
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The present invention relates to a compound represented by formula (I) wherein X is selected from the group of formulae (II) to (IV) wherein R1 is H or C1-C50 chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1); or R1 is a C3-C28 moiety which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); R2 is H; or R2 is a Mono-phosphate, Di-phosphate, Tri-phosphate or phosphoramidite moiety; or R2 is -Y-X or -Y-L-Y1- X; Y and Y1 are independently from each other a single bond or a functional connecting moiety, X is a colloid-active compound (CA) or a fluorescence marker (FA) or a polynucleotide moiety having up to 50 nucleotide residues, preferably 10 to 25 nucleotides, especially a polynucleotide having an antisense or antigen effect; L is a linker by means of which Y and X are covalently linked together; R3 and R4 represent independently from each other a C1-C28-alkyl moiety which may optionally be substituted or interrupted by one or more heteroatom(s) and/or functional group(s);or R3 and R4 form a ring having at least 5 members, preferably a ring having 5 to 8 carbon atoms and wherein the ring may be substituted or interrupted by one or more hetero atom(s) and/or functional group(s); or R3 and R4 represent independently from each other a C1-C28-alkyl moiety substituted with one or more moieties selected from the group -Y-X or -Y-L-Y1-X; or R3 and R4 represent independently from each other -Y-X or -Y-L-Y1- X; R5 and R6 represent independently from each other a C1-C28-alkyl moiety which may optionally be substituted or interrupted by one or more heteroatom(s) and/or functional group(s); or R5 and R6 represent independently from each other a C1-C28-alkyl moiety substituted with one or more moieties selected from the group -Y-X or -Y-L-Y1-X; or R5 and R6 form a ring having at least 5 members, preferably a ring having 5 to 18 carbon atoms and wherein the ring may be substituted or interrupted by one or more hetero atom(s) and/or functional group(s); and/or one or more moieties selected from the group -Y-X or -Y-L-Y1- X; R5 and R6 represent independently from each other -Y-X or -Y-L-Y1- X; R7 is a hydrogen atom or -O-R8; R8 is H or C1-C28 chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1); or R8 is -Y-X or -Y-L-Y1- X, with the proviso that R1 and R2 are not both H and/or with the proviso that the compound comprises at least two chains each of which having 4 or more carbon atoms.
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Paragraph 0080
(2014/05/06)
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- Use of fosfluridine tidoxil (FT) for the treatment of intraepithelial proliferative diseases
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The present invention is directed to the systemic administration of Fosfluridine Tidoxil, (5-fluorouridine)-5′-phosphoric acid (3-dodecylmercapto-2-decyloxy)propylester or a salt thereof, for the treatment of intraepithelial proliferative diseases such as actinic keratosis. The Fosfluridine Tidoxil can be systemically administered alone or in combination with topical treatment agents.
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Page/Page column 2-3
(2008/06/13)
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- Compositions and methods for targeted enzymatic release of cell regulatory compounds
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Novel pro-drugs and methods for their use to alter the growth and biological characteristics of living cells, tissues, or whole organisms are described. The methods allow for selective activation of the pro-drugs at or near transformant host cells expressing a gene for an enzyme that activates the pro-drugs. Pro-drugs according to a preferred embodiment of the invention are conjugates of a bioactive compound and a chemical group that is capable of being cleaved from the bioactive compound by action of an enzyme. Methods according to this invention include, (a) introducing into targeted cells a gene encoding an enzyme and (b) administering a pro-drug, wherein the enzyme releases the pro-drug from conjugation. In a preferred embodiment of the invention, the gene encoding the enzyme is a marker gene.
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(2010/02/05)
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- Prodrugs activated by targeted catalytic proteins
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Prodrugs that are activated by and conjugated to a catalytic antibody conjugated to a moiety that binds to a tumor cell population are provided.
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- In vitro and in vivo antitumor activity of immunoconjugates prepared by linking 5-Fluorouridine to antiadenocarcinoma monoclonal antibody
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5-Fluorouridine (5-FUr), a cytotoxic antitumoral agent not in clinical use because of its systemic toxicity, and AR-3, a monoclonal antibody specific to a human colorectal adenocarcinoma, were covalently linked via two different strategies. 5-FUr was 5' succinilated after protection of the secondary hydroxyl groups and the carboxylate derivative was then activated as N- hydroxysuccinimidyl ester in order to react with the amino groups present in the monoclonal antibody, giving an amide linkage. Alternatively, a 5-FUr immunoconjugate containing an acid-clearable hydrazone bond was formed from the reaction between an acyl hydrazide derivative of 5-FUr and a periodate oxydized antibody with approximately 12 aldehyde groups in its carbohydrate region. An average of 9 to 12 drug molecules were attached to the antibody. In a cytotoxic assay on the human colorectal carcinoma cell line HT-29, the hydrazone containing drug conjugate was equally active as the succinylamido conjugate and the free drug. However, ELISA showed that while in the case of the succinylamido conjugate the Mab immunoreactivity was not affected after conjugation, there was a significant loss of reactivity in the acid cleavable conjugate. In a model of a disseminated intraabdominal carcinomatosis by HT-29 intraperitoneal graft in nude mice, the 5-FUr immunoconjugate selected was more effective than the unconjugated drug in medium-term therapy (21 days after the graft and 16 days after drug treatment), albeit in the longer period the efficacy of the two formulations was similar. The toxic effect of the drug-conjugate in vivo was much weaker, demonstrating its clear advantage over the drug, in terms of pharmacological efficacy.
- Brusa,Dosio,Coppo,Pacchioni,Arpicco,Crosasso,Cattel
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- 5-fluorouracil, 2'-deoxy-5-fluorouridine and 1-carbomoyl-5-fluorouracil compounds
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A 5-fluorouracil derivative represented by the formula (1): STR1 wherein A represents a group represented by STR2 wherein R1 represents a hydrogen atom or OR5 group, R2, R3 and R5 may be the same or different and each represents a hydrogen atom or a group represented by the following formula (2): STR3 wherein R6 represents an acyl group, R7 represents a hydrogen atom, a straight or branched alkyl group, a cycloalkyl group, an aralkyl group, a lower alkenyl group or a phenyl group, and n is an integer of 0 to 6, provided that at least one of R2, R3 and R5 is a group represented by the formula (2), and the case wherein R2 and R5 are both hydrogen atoms is excluded, R4 represents a group represented by the formula (2), and X represents an alkylene group or a cycloalkylene group, and an antitumor agent containing the same as an active ingredient.
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- p-Methoxybenzyl as a New N3-Imide Protecting Group of 5-Fluorouridine and Its Application to the Synthesis of 5'-O-Acryloyl-5-fluorouridine
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5'-O-Acryloyl-5-fluorouridine was prepared by use of p-methoxybenzyl (PMB) group as a new N3-imide protecting group of 5-fluorouridine.A chemoselective method for protection has been developed by use of ethyldiisopropylamine as a base and depro
- Akiyama, Takahiko,Kumegawa, Masahiro,Takesue, Yasuhiro,Nishimoto, Hiroyuki,Ozaki, Shoichiro
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p. 339 - 342
(2007/10/02)
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- 17O NMR of Nucleosides. 3 - Chemical Shifts of Substituted Uridines and Ribothymidines
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Uridine and ribothymidine derivatives, bearing different substituents at C-5 and enriched (Ca 50percent) with 17O in the O-4 and O-2 carbonyls, have been studied via 17O NMR in both acetonitrile and aqueous solvents.The solvent shift differences between acetonitrile and water at O-4 (30-42 ppm) and O-2 (13-16 ppm) vary significantly from each other, but the chemical shift changes induced by changing the substituent at C-5 correlated well only with the O-4 shifts and the electron-withdrawing ability of the substituent.Examination of the 17O shifts of model compounds reconfirms the predominance of keto tautomers for both carbonyls.The significance of the solvent shifts and substituent shifts are discussed with respect to the electronic structure of the nucleoside base rings, and with respect to the hydrogen-bonding abilities of the carbonyl groups.Other nucleoside derivatives studied include those in which the 17O enrichment is in the ring linking the base to the sugar moiety in a pyrimidine cyclonucleoside, in the sugar hydroxy groups and in the phosphodiester linkage of a highly strained ring system in a nucleoside cyclic monophosphate.
- Schwartz, Herbert M.,MacCoss, Malcolm,Danyluk, Steven S.
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p. 885 - 894
(2007/10/02)
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- Nucleosides. 114. 5'-O-Glucuronides of 5-Fluorouridine and 5-Fluorocytidine. Masked Precursors of Anticancer Nucleosides
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5'-O-Glucuronides of anticancer nucleosides, 5-fluorouridine and 5-fluorocytidine, were synthesized by three different methods.The best preparative procedure was the one starting from benzyl 5-O-(methyl-2',3',4'-tri-O-acetyl-β-D-glucopyranosyluronate)-2,3
- Watanabe, K. A.,Matsuda, A.,Halat, M. J.,Hollenberg, D. H.,Nisselbaum, J. S.,Fox, J. J.
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p. 893 - 897
(2007/10/02)
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- 5'-Deoxy-5-fluoropyrimidine nucleosides
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Novel 5'-deoxy-5-fluoropyrimidine nucleosides are potent anti-tumor agents. Preferred compounds are 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine.
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