- Synthesis and antitumor activity of a heterodinucleotide of BVDU and gemcitabine
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A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5′,5′-pyrophospate bridge (BVDUp2dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp2dFdC showed a cytotoxicity similar to that of Gemcitabine. Copyright Taylor & Francis Group, LLC.
- Cappellacci,Franchetti,Vita,Petrelli,Grifantini
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- Gemcitabine-Ibandronate Conjugate Enables the Bone-Targeted Combination Therapy in Bone Cancer: Synthesis and Efficacy in Combination with Docetaxel
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Patients with cancer-induced bone disease, including primary bone cancers such as osteosarcoma (OS) and metastases from other tissues of origin, present a high unmet medical need. We present a potential therapeutic approach built upon a proven bone-targeting bisphosphonate conjugate platform with the known synergies of gemcitabine (GEM) and docetaxel (DTX). The synthesis of rationally designed GEM-IB, the conjugate of GEM-5′-phosphate with ibandronate (IB), is presented. GEM-IB as a single agent or in combination with DTX demonstrated reduced tumor burden, preservation of the bone architecture, and improved the survival in a murine model of OS. This is the first demonstration of a bone-targeting conjugate in combination with a second drug to create effective drug ratios in the bone compartment.
- Farrell, Kristen B.,Zinnen, Shawn,Thamm, Douglas H.,Karpeisky, Alexander
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p. 2530 - 2539
(2021/11/30)
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- New Mechanism of Gemcitabine and Its Phosphates: DNA Polymerization Disruption via 3′-5′ Exonuclease Inhibition
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Gemcitabine (dFdC), a modified deoxycytidine (dC) widely used in tumor treatment, is a prodrug that is phosphorylated to generate mono-, di-, and triphosphates. The triphosphate (dFdCTP) is incorporated into DNA to terminate DNA synthesis in cancer. Some incorporated dFdC nucleotides can be partially removed by the 3′-5′ exonuclease activity, namely its editing function, and the others escape the editing. However, whether there is an active mechanism for dFdC to escape the editing remains unclear. We have first discovered that unlike dFdC, its mono-, di-, and triphosphates can inhibit the 3′-5′ exonuclease of DNA polymerase I, suppress editing, and allow the active escaping mechanism, whereas its polymerase activity is not remarkably affected. As such, these phosphates can prevent the removal of the incorporated dFdC residue, thereby actively blocking DNA extension and synthesis. The inhibition efficiency of these phosphates follows the increased order of the mono-, di-, and triphosphates of gemcitabine (dFdC a novel anticancer mechanism of gemcitabine and its phosphate derivatives.
- Huang, Zhen,Li, Chuncheng,Li, Na,Luo, Danyan,Tang, Shuo,Yang, Shuzhang
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p. 4344 - 4352
(2020/12/03)
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- Theranostic nanoparticles enabling the release of phosphorylated gemcitabine for advanced pancreatic cancer therapy
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Gemcitabine (GEM) has been the recommended first-line drug for patients with pancreatic ductal adenocarcinoma cancer (PDAC) for the last twenty years. However, GEM-based treatment has failed in many patients because of the drug resistance acquired during
- Ding, Xiaoyi,Huang, Wei,Jiang, Chen,Li, Fuyou,Sun, Tao,Wang, Qingbing,Wang, Zhongmin,Wu, Zhiyuan,Zhu, Xingjun
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p. 2410 - 2417
(2020/04/08)
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- Efficient synthesis of gemcitabine 5′-O-triphosphate using gemcitabine 5′-O-phosphoramidate as an intermediate
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A new efficient approach for the synthesis of gemcitabine triphosphate has been developed. The method is based on the ring-opening reaction of 2-cyanoethoxy-2-oxo-1,3,2-oxathiaphospholane with protected gemcitabine in the presence of DBU. Subsequent treatment of gemcitabine monophosphate with DCC in the presence of ammonia provides gemcitabine 5′-O-phosphoramidate. Finally, this compound, on reaction with pyrophosphate, furnishes gemcitabine 5′-triphosphate in 50% yield. Georg Thieme Verlag Stuttgart. New York.
- Kaczmarek, Renata,Radzikowska, Ewa,Baraniak, Janina
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supporting information
p. 1851 - 1854
(2014/08/18)
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- Fully automated continuous meso-flow synthesis of 5′-nucleotides and deoxynucleotides
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The first continuous meso-flow synthesis of natural and non-natural 5′-nucleotides and deoxynucleotides is described, representing a significant advance over the corresponding in-flask method. By means of this meso-flow technique, a synthesis with time consumption and high-energy consumption becomes facile to generate products with great efficiency. An abbreviated duration, satisfactory output, and mild reaction conditions are expected to be realized under the present procedure.
- Zhu, Chenjie,Tang, Chenglun,Cao, Zhi,He, Wei,Chen, Yong,Chen, Xiaochun,Guo, Kai,Ying, Hanjie
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p. 1575 - 1581
(2015/02/19)
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- Two thymidine kinases and one multisubstrate deoxyribonucleoside kinase salvage DNA precursors in Arabidopsis thaliana
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Deoxyribonucleotides are the building blocks of DNA and can be synthesized via de novo and salvage pathways. Deoxyribonucleoside kinases (EC 2.7.1.145) salvage deoxyribonucleosides by transfer of a phosphate group to the 5' of a deoxyribonucleoside. This salvage pathway is well characterized in mammals, but in contrast, little is known about how plants salvage deoxyribonucleosides. We show that during salvage, deoxyribonucleosides can be phosphorylated by extracts of Arabidopsis thaliana into corresponding monophosphate compounds with an unexpected preference for purines over pyrimidines. Deoxyribonucleoside kinase activities were present in all tissues during all growth stages. In the A. thaliana genome, we identified two types of genes that could encode enzymes which are involved in the salvage of deoxyribonucleosides. Thymidine kinase activity was encoded by two thymidine kinase 1 (EC 2.7.1.21)-like genes (AtTK1a and AtTK1b). Deoxyadenosine, deoxyguanosine and deoxycytidine kinase activities were encoded by a single AtdNK gene. T-DNA insertion lines of AtTK1a and AtTK1b mutant genes had normal growth, although AtTK1a AtTK1b double mutants died at an early stage, which indicates that AtTK1a and AtTK1b catalyze redundant reactions. The results obtained in the present study suggest a crucial role for the salvage of thymidine during early plant development. 2012 The Authors Journal compilation
- Clausen, Anders R.,Girandon, Lenart,Ali, Ashfaq,Knecht, Wolfgang,Rozpedowska, Elzbieta,Sandrini, Michael P. B.,Andreasson, Erik,Munch-Petersen, Birgitte,Piskur, Jure
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p. 3889 - 3897
(2013/01/13)
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- Inactivation of lactobacillus leichmannii ribonucleotide reductase by 2',2'-difluoro2'-deoxycytidine s'-triphosphate: Covalent modification
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Ribonucleotide reductase (RNR) from Lactobacillus leichmannii, a 76 kDa monomer using adenosylcobalamin (AdoCbl) as a cofactor, catalyzes the conversion of nucleoside triphosphates to deoxynucleotides and is rapidly ( 3H]- and [5-3H]F2CTP were synthesized and used independently to inactivate RNR. Sephadex G-50 chromatography of the inactivation mixture revealed that 0.47 equiv of a sugar was covalently bound to RNR and that 0.71 equiv of cytosine was released. Alternatively, analysis of the inactivated RNR by SDS-PAGE without boiling resulted in 33% of RNR migrating as a 110 kDa protein. Inactivation of RNR with a mixture of [1'-3H]F2CTP and [1'-2H]F 2CTP followed by reduction with NaBH4, alkylation with iodoacetamide, trypsin digestion, and HPLC separation of the resulting peptides allowed isolation and identification by MALDI-TOF mass spectrometry (MS) of a 3H/2H-labeled peptide containing C731 and C736 from the C-terminus of RNR accounting for 10% of the labeled protein. The MS analysis also revealed that the two cysteines were cross-linked to a furanone species derived from the sugar of F2CTP. Incubation of [1-3H]F2CTP with C119S-RNR resulted in 0.3 equiv of sugar being covalently bound to the protein, and incubation with NaBH4 subsequent to inactivation resulted in trapping of 2'-fluoro-2'-deoxycytidine. These studies and the ones in the preceding paper (DOI: 10.1021/bi9021318) allow proposal of a mechanism of inactivation of RNR by F2CTP involving multiple reaction pathways. The proposed mechanisms share many common features with F2CDP inactivation of the class I RNRs.
- Lohman, Gregory J.S.,Stubbe, Joanne
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experimental part
p. 1404 - 1417
(2011/02/21)
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- Facile small scale synthesis of nucleoside 5′-phosphate mixtures
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We present a facile method to phosphorylate small amounts of nucleosides (0.05 mol) into mixtures of their 5′-mono-, di-, and triphosphates in a one-pot reaction. The nucleosides were first converted into their dichlorophosphates using a large excess (15-18 equivalents) of phosphorous oxychloride in trimethylphosphate. The large excess resulted in good dichlorophosphate yields (46-76%) for the four nucleosides tested. Upon the addition of tributylammonium-phosphate with additional tributylamine (20 equivalents both), the dichlorophosphate was converted into a mixture containing equal amounts of the mono-, di-, and triphosphate. The presented method was successfully applied to synthesize mixtures of stable isotope labeled nucleotides, which can be used as internal standards in quantitative mass spectrometric assays.
- Jansen, Robert S.,Rosing, Hilde,Schellens, Jan Hm,Beijnen, Jos H.
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experimental part
p. 14 - 26
(2010/07/06)
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- Synthesis of gemcitabine triphosphate (dFdCTP) as a tris(triethylammonium) salt
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First synthesis of gemcitabine triphosphate (dFdCTP) as a tris(triethylammonium) salt is reported.
- Risbood, Prabhakar A.,Kane Jr., Charles T.,Hossain, Md. Tafazzal,Vadapalli, Sudhakarrao,Chadda, Satish K.
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p. 2957 - 2958
(2008/12/22)
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