- DNA Trojan Horses: Self-Assembled Floxuridine-Containing DNA Polyhedra for Cancer Therapy
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Based on their structural similarity to natural nucleobases, nucleoside analogue therapeutics were integrated into DNA strands through conventional solid-phase synthesis. By elaborately designing their sequences, floxuridine-integrated DNA strands were sy
- Mou, Quanbing,Ma, Yuan,Pan, Gaifang,Xue, Bai,Yan, Deyue,Zhang, Chuan,Zhu, Xinyuan
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- Preparation of oligomeric 2'-deoxy-5-fluorouridylate of defined length and backbone composition: A novel pro-drug form of the potent anti-cancer drug 2'-deoxy-5-fluorouridylate
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A recursive protection scheme for FdUMP is employed by synthesizing oligonucleotides consisting of only FdU. 3'-O-exonuclease action releases FdUMP and a shortened oligonucleotide from which further exonuclease action releases more FdUMP. Such oligonucleo
- Gmeiner,Sahasrabudhe,Pon,Sonntag,Srinivasan,Iversen
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- Discovery of an Orally Active and Liver-Targeted Prodrug of 5-Fluoro-2′-Deoxyuridine for the Treatment of Hepatocellular Carcinoma
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We report a series of novel O-(substituted benzyl) phosphoramidate prodrugs of 5-fluoro-2′-deoxyuridine for the treatment of hepatocellular carcinoma. Through structure optimization, the o-methylbenzyl analog (1t) was identified as an orally bioavailable and liver-targeted lead compound. This lead prodrug is well-tolerated at a dose up to 3 g/kg in Kuming mice via oral administration. An efficacy study demonstrated that it possesses good inhibitory effect (61.67% and 72.50%, respectively) on tumor growth in a mouse xenograft model. A metabolism study in Sprague-Dawley rats suggested that 1t can release the desired 5′-monophosphate in the liver with high liver-targeting index.
- Peng, Youmei,Yu, Wenquan,Li, Ertong,Kang, Jinfeng,Wang, Yafeng,Yang, Qinghua,Liu, Bingjie,Zhang, Jingmin,Li, Longyu,Wu, Jie,Jiang, Jinhua,Wang, Qingduan,Chang, Junbiao
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- Fluorine at the C5 Position of 2′-Deoxyuridine Enhances Repair of a O4-Methyl Adduct by O6-Alkylguanine DNA Alkyltransferases
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Alkylation damage at the O6- and O4-atoms of 2′-deoxyguanosine (dG) and thymidine (T), respectively, can be removed by O6-alkylguanine-DNA alkyltransferases (AGTs). Previous studies have shown that human AGT (hAGT) repairs
- Sacre, Lauralicia,Wilds, Christopher J.
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- Selective targeting of 2′-deoxy-5-fluorouridine to urokinase positive malignant cells in vitro
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A urokinase targeting conjugate of 2′-deoxy-5-fluorouridine (5-FUdr) was synthesized and tested for tumor-cell selective cytotoxicity in vitro. The 5-FUdr prodrug 2′-deoxy-5-fluoro-3′-O-(3-carboxypropanoyl)uridine (5-FUdrsuccOH) containing an ester-labile
- Vine, Kara L.,Locke, Julie M.,Bremner, John B.,Pyne, Stephen G.,Ranson, Marie
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- γ-Radiolysis of 2'-deoxy-5-fluorouridine derivatives with sulfur-containing substituents
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2'-Deoxy-5-fluorouridine (5-FUdR) derivatives having various types of sulfur-containing substituents at the 5'-O-position were synthesized and their γ-radiolyses were studied in aqueous solutions. The γ-radiolysis of compounds having 1,3-dithiol-2-yl and 1,3-dithian-2-yl substituents at the 5'-O-position efficiently gave 5-FUdR, specifically via the attack of hydroxyl radical. On the other hand, the γ-radiolysis of a compound having a sulfonylmethyl substituent at the 5'-O-position gave less efficiently 5-FUdR, specifically via the attack of the hydrated electron. The mechanistic features of these reactions are discussed.
- Kuroda,Hisamura,Nakamizo,Otsuji
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- Floxuridine Homomeric Oligonucleotides “Hitchhike” with Albumin In Situ for Cancer Chemotherapy
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Automated attachment of chemotherapeutic drugs to oligonucleotides through phosphoramidite chemistry and DNA synthesis has emerged as a powerful technology in constructing structure-defined and payload-tunable oligonucleotide–drug conjugates. In practice,
- Jin, Cheng,Zhang, Hui,Zou, Jianmei,Liu, Yan,Zhang, Lin,Li, Fengjie,Wang, Ruowen,Xuan, Wenjing,Ye, Mao,Tan, Weihong
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- Enhancing antitumor efficacy of nucleoside analog 5-fluorodeoxyuridine on her2-overexpressing breast cancer by affibody-engineered DNA nanoparticle
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Background: Chemotherapy, as an adjuvant treatment strategy for HER2-positive breast cancer, can effectively improve clinical symptoms and overcome the drug resistance of therapeutic monoclonal antibodies. Nucleoside analogues are a class of traditional c
- Chen, Shengxi,Du, Jie,Han, Mengnan,Li, Wei,Yang, Xueli,Zhang, Chao,Zhang, Fanghua,Zhang, Honglei
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- Targeting nano carrier bearing nucleoside anti-tumor drugs and preparation method and application thereof
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The invention provides a targeting nano carrier bearing nucleoside anti-tumor drugs and preparation method and application thereof. The targeting nano carrier comprises DNA tetrahedron, Affibody molecule and nucleoside anti-tumor drugs. The preparation me
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Paragraph 0080-0082; 0084
(2019/02/04)
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- THERAPEUTIC NANOCONJUGATES AND USES THEREOF
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The present invention relates to nanostructured conjugates, more specifically to nanostructured fusion proteins suitable for the selective delivery of their conjugated therapeutic agents to specific cell and tissue types. It also relates to nanoparticles comprising such nanostructured proteins and the therapeutic uses thereof.
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Page/Page column 64-65
(2019/01/30)
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- 5-FLUOROURIDINE MONOPHOSPHATE CYCLIC TRIESTER COMPOUNDS
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Provided herein are 5-fluorouridine monophosphate cyclic triester compounds, their preparation and their uses, such as treating hepatocellular carcinoma and other types of cancer.
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Paragraph 0134
(2019/04/18)
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- 3'- O - And 5'- O -Propargyl Derivatives of 5-Fluoro-2'-Deoxyuridine: Synthesis, Cytotoxic Evaluation and Conformational Analysis
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A series of new 3'-O- and 5'-O-propargyl derivatives of 5-fluoro-2'-deoxyuridine (1-4) was synthesized by means of propargyl reaction of properly blocked nucleosides (2,4), followed by the deprotection reaction with ammonium fluoride. The synthesized propargylated 5-fluoro-2'-deoxyuridine analogues (1-4) were evaluated for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7), using the sulforhodamine B (SRB) assay. The highest activity and the best SI coefficient in all of the investigated cancer cells were displayed by 3'-O-propargyl-5-fluoro-2'-deoxyuridine (1), and its activity was higher than that of the parent nucleoside. The other new compounds exhibited moderate activity in all of the used cell lines.
- Baraniak, Dagmara,Baranowski, Daniel,Ruszkowski, Piotr,Boryski, Jerzy
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p. 178 - 194
(2016/04/19)
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- Anti-flavivirus Activity of Different Tritylated Pyrimidine and Purine Nucleoside Analogues
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A series of tritylated and dimethoxytritylated analogues of selected pyrimidine and purine nucleosides were synthesized and evaluated for their in vitro inhibitory activity against two important members of the genus Flavivirus in the Flaviviridae family, the yellow fever (YFV) and dengue viruses (DENV). Among all compounds tested, the 5′-O-tritylated and the 5′-O-dimethoxytritylated 5-fluorouridine derivatives exerted potency against YFV. Interestingly in the series of purine analogues, the 5′O, N-bis-tritylated fludarabine derivative revealed strong inhibitory activity against DENV at μm concentrations, however significantly weaker potency against YFV.
- McGuigan, Christopher,Serpi, Michaela,Slusarczyk, Magdalena,Ferrari, Valentina,Pertusati, Fabrizio,Meneghesso, Silvia,Derudas, Marco,Farleigh, Laura,Zanetta, Paola,Bugert, Joachim
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p. 227 - 235
(2016/07/07)
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- Delivery of floxuridine derivatives to cancer cells by water-soluble organometallic cages
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The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (pPriC6H4Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) or 5,8-dioxydo-1,4-naphthoquinonato (donq) bridges, in the presence of a pyrenyl-nucleoside derivatives (pyreneR), affords the triangular prismatic host-guest compounds [(pyrene-R)?Ru6(pPriC 6H4Me)6(tpt)2(dobq) 3]6+ ([(pyrene-R)?1]6+) and [(pyrene-R)?Ru6(pPriC6H4Me) 6(tpt)2(donq)3]6+ ([(pyrene-R)?2]6+), respectively. The inclusion of six monosubstitutedpyrenyl-nucleosides (pyrene-R1 = 5′-(1-pyrenyl butanoate)-2′-deoxyuridine, pyrene-R2 = 5-fluoro-5′-(1-pyrenyl butanoate)-2′-deoxyuridine, pyrene-R3 = 5′-{N-[1-oxo-4-(1-pyrenyl) butyl]-glycyl}-2′-deoxyuridine, pyrene-R4 = 5-fluoro-5′-{N-[1-oxo-4- (1-pyrenyl)butyl]-glycyl}-2′-deoxyuridine, pyrene-R5 = 5-fluoro-5′-{N-[1-oxo-4-(1-pyrenyl)butyl]-phenylalanyl} -2′-deoxyvuridine, pyrene-R6 = 5-fluoro-5′-{N-[1-oxo-4-(1-pyrenyl) butyl]-phenylalanyl}-2′-deoxyuridine) has been accomplished. The carceplex nature of [(pyrene-R)?1]6+ with the pyrenyl moiety firmly encapsulated in the hydrophobic cavity of the cage with the nucleoside groups pointing outward was confirmed by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS), while the host-guest nature of [(pyrene-R)?2] 6+ was studied in solution by NMR techniques. In contrast to the floxuridine compounds used in the clinic, the host-guest complexes are highly water-soluble. Consequently, the cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 and A2780cisR cancer cells. All the host-guest systems are more cytotoxic than the empty cages alone [1][CF3SO3]6 (IC50 = 23 μM) and [2][CF3SO3]6 (IC50 = 10 μM), the most active compound [pyrene-R4?1][CF3SO3] 6being 2 orders of magnitude more cytotoxic (IC50 = 0.3 μM) on these human ovarian cancer cell lines (A2780 and A2780cisR).
- Yi, Jeong Wu,Barry, Nicolas P. E.,Furrer, Mona A.,Zava, Olivier,Dyson, Paul J.,Therrien, Bruno,Kim, Byeang Hyean
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experimental part
p. 461 - 471
(2012/06/04)
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- Synthesis and enzymatic characterization of P1-thio-P2-oxo trideoxynucleoside diphosphates having AZT, FdU, or dT at the 3'-position
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Model compounds for oligonucleotide-prodrugs, P1-thio-P2-oxo-tri-deoxyribonucleoside diphosphates: d[G5C0X] and d[TsA0X] (X = AZT, FdU or dT) have been prepared, and their hydrolyses by snake venom phosphodiesterase and nuclease S1 are described.
- Oetvoes, Laszlo,Bajor, Zoltan,Kraicsovits, Ferenc,Sagi, Gyula,Tegyey, Zsuzsanna
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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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- Oligonucleotides containing 5-fluorouracil
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A homo-oligonucleotide of between 2 and 26 monomers of 5-fluorouridine 5'-monophosphate or 5-fluorodeoxyuridine 5'-monophosphate covalently linked via 3'- to 5'-phosphodiester linkages, where at the 3'- or 5'- terminus there is covalently linked a molecul
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- Protected 5-fluoro-2'-deoxyuridine monophosphate for solution-phase synthesis of oligonucleotides
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In order to obtain new building blocks for oligonucleotide (ODN) solution synthesis we are describing the synthesis of the protected dinucleotide 3a carrying 5-fluorouracil and thymine as an example of future development in this field. The synthesis start
- Mazzei,Grandi,Balbi,Abramova,Damonte,Silvestro
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p. 793 - 797
(2007/10/02)
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