- Phosphotyrosine prodrugs: design, synthesis and anti-STAT3 activity of ISS-610 aryloxy triester phosphoramidate prodrugs
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Unmasked phohate groups of phosphotyrosine-containing molecules carry two negative charges at physiological pH, which compromise their (passive) cellular uptake. Also, these phosphate groups are often cleaved off by phosphatases. Together, these ultimatel
- Miccoli, Ageo,Dhiani, Binar A.,Mehellou, Youcef
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- Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate
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ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs phosphate masking groups capable of providing more favorable druglike properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein, we describe the application of phosphoramidate chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac3ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines. These results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.
- Morozzi, Chiara,Sedláková, Jana,Serpi, Michaela,Avigliano, Marialuce,Carbajo, Rosangela,Sandoval, Lucia,Valles-Ayoub, Yadira,Crutcher, Patrick,Thomas, Stephen,Pertusati, Fabrizio
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p. 8178 - 8193
(2019/09/10)
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- MONOSACCHARIDE PHOSPHORAMIDATE PRODRUGS
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The present disclosure provides monosaccharide phosphoramidate prodrugs of monosaccharide monophosphates. The present disclosure further provides methods of treating diseases of conditions such as congenital disorders of glycosylation comprising administering the monosaccharide phosphoramidate prodrugs of the present disclosure to a patient in need thereof.
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Paragraph 0149; 0156-0158
(2019/07/19)
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- 4'-THIO-NUCLEOTIDE AND -NUCLEOSIDE PRODRUGS FOR THE TREATMENT OF CANCER
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The present disclosure is concerned with 4'-thio nucleotide and nucleoside compounds for the treatment of various cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Paragraph 00423; 00448
(2019/11/12)
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- FLOXURIDINE SYNTHESIS
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The present invention relates to a process for the preparation of floxuridine, said process comprising reacting a compound of Formula la with a compound of Formula lla in the presence of an acid Al to provide a compound of Formula Ilia in substantially diastereomerically pure form. Floxuridine may be useful as an anti-cancer drug. Floxuridine may also be useful in the preparation of other anti-cancer drugs, e.g. NUC-3373.
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Page/Page column 34-37
(2019/04/11)
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- PHOSPHORAMIDATE DERIVATIVES OF 5 - FLUORO - 2` - DEOXYURIDINE FOR USE IN THE TREATMENT OF CANCER
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Phosphoramidate derivatives of 5-fluoro-2′-deoxyuridine are disclosed for use in the treatment of cancer, especially in the treatment of cancer where the patient shows resistance, for example, in a patient with cells with a lowered level of nucleoside tra
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Paragraph 0092
(2014/03/24)
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- Application of ProTide technology to gemcitabine: A successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development
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Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents.
- Slusarczyk, Magdalena,Lopez, Monica Huerta,Balzarini, Jan,Mason, Malcolm,Jiang, Wen G.,Blagden, Sarah,Thompson, Emely,Ghazaly, Essam,McGuigan, Christopher
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supporting information
p. 1531 - 1542
(2014/03/21)
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- Synthesis and Biological Evaluation of Purine 2′-Fluoro-2′-deoxyriboside ProTides as Anti-influenza Virus Agents
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2′-Fluoro-2′-deoxyguanosine has been reported to have potent anti-influenza virus activity invitro and invivo. Herein we describe the synthesis and biological evaluation of 6-modified 2′-fluoro-2′-deoxyguanosine analogues and their corresponding phosphora
- Meneghesso, Silvia,Vanderlinden, Evelien,Brancale, Andrea,Balzarini, Jan,Naesens, Lieve,Mcguigan, Christopher
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supporting information
p. 415 - 425
(2013/08/25)
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- 4'-AZIDO, 3'-FLUORO SUBSTITUTED NUCLEOSIDE DERIVATIVES AS INHIBITORS OF HCV RNA REPLICATION
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The present invention relates to the use of nucleoside derivatives of formula (I) wherein the symbols are as the specification, and of pharmaceutically acceptable salts thereof and to pharmaceutical compositions containing such compounds.
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- PHOSPHORAMIDATE DERIVATIVES OF 5 - FLUORO - 2 ' - DEOXYURIDINE FOR USE IN THE TREATMENT OF CANCER
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Phosphoramidate derivatives of 5-fluoro-2'-deoxyuridine are disclosed for use in the treatment of cancer, especially in the treatment of cancer where the patient shows resistance, for example, in a patient with cells with a lowered level of nucleoside transporter proteins and/or with nucleoside kinase-deficient cells and/or with mycoplasma-infected cells and/or with cells with a raised level of thymidylate synthase.
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Page/Page column 25
(2012/09/21)
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- Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus
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Uridine-based nucleoside analogues have often been found to have relatively poor antiviral activity. Enzymatic assays, evaluating inhibition of influenza virus RNA polymerase, revealed that some uridine triphosphate derivatives displayed inhibitory activity on UTP incorporation into viral RNA. Here we report the synthesis, antiviral activity and enzymatic evaluation of novel ProTides designed to deliver the activated (monophosphorylated) uridine analogues inside the influenza virus-infected cells. After evaluation of the activation profile we identified two ProTides with moderate antiviral activity in MDCK cells (23a, EC99=49±38μM and 23b, EC99≥81μM) while the corresponding nucleoside analogue (2'-fluoro-2'-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation.
- Meneghesso, Silvia,Vanderlinden, Evelien,Stevaert, Annelies,McGuigan, Christopher,Balzarini, Jan,Naesens, Lieve
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experimental part
p. 35 - 43
(2012/07/28)
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- Design, synthesis and biological evaluation of 2′-deoxy-2′, 2′-difluoro-5-halouridine phosphoramidate ProTides
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We report the synthesis of a series of novel 2′-deoxy-2′, 2′-difluoro-5-halouridines and their corresponding phosphoramidate ProTides. All compounds were evaluated for antiviral activity and for cellular toxicity. Interestingly, 2′-deoxy-2′,2′-difluoro-5-iodo- and -5-bromo-uridines showed selective activity against feline herpes virus replication in cell culture due to a specific recognition (activation) by the virus-encoded thymidine kinase.
- Quintiliani, Maurizio,Persoons, Leentje,Solaroli, Nicola,Karlsson, Anna,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,McGuigan, Christopher
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experimental part
p. 4338 - 4345
(2011/09/12)
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- The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2′-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes
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A novel phosphoramidate nucleotide prodrug of the anticancer nucleoside analogue 5-fluoro-2′-deoxyuridine (5-FdUrd) was synthesized and evaluated for its cytostatic activity. Whereas 5-FdUrd substantially lost its cytostatic potential in thymidine kinase (TK)-deficient murine leukaemia L1210 and human lymphocyte CEM cell cultures, NUC-3073 markedly kept its antiproliferative activity in TK-deficient tumour cells, and thus is largely independent of intracellular TK activity to exert its cytostatic action. NUC-3073 was found to inhibit thymidylate synthase (TS) in the TK-deficient and wild-type cell lines at drug concentrations that correlated well with its cytostatic activity in these cells. NUC-3073 does not seem to be susceptible to inactivation by catabolic enzymes such as thymidine phosphorylase (TP) and uridine phosphorylase (UP). These findings are in line with our observations that 5-FdUrd, but not NUC-3073, substantially loses its cytostatic potential in the presence of TP-expressing mycoplasmas in the tumour cell cultures. Therefore, we propose NUC-3073 as a novel 5-FdUrd phosphoramidate prodrug that (i) may circumvent potential resistance mechanisms of tumour cells (e.g. decreased TK activity) and (ii) is not degraded by catabolic enzymes such as TP which is often upregulated in tumour cells or expressed in mycoplasma-infected tumour tissue.
- Vande Voorde, Johan,Liekens, Sandra,McGuigan, Christopher,Murziani, Paola G.S.,Slusarczyk, Magdalena,Balzarini, Jan
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experimental part
p. 441 - 452
(2012/01/14)
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- PHOSPHORAMIDATE DERIVATIVES OF GUANOSINE NUCLEOSIDE COMPOUNDS FOR TREATMENT OF VIRAL INFECTIONS
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Phosphoramidate compounds derived from guanine bases having enhanced therapeutic potency are provided, and these compounds in particular have enhanced potency with respect to treatment of viral infections, such as hepatitis C virus. Pharmaceutical compositions, methods of preparing the compounds, and methods of using the compounds and compositions to treat viral infections are also provided.
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Page/Page column 89; 91
(2010/08/04)
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- URACYL CYCLOPROPYL NUCLEOTIDES
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Compounds of the formula (I) including any possible stereoisomers thereof, wherein: R1 is hydrogen or halo; R4 is a monophosphate, diphosphate or triphosphate ester; or R4 is a group of formula (II) R7 is option
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- The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition
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Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated. ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types -1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.
- Derudas, Marco,Carta, Davide,Brancale, Andrea,Vanpouille, Christophe,Lisco, Andrea,Margolis, Leonid,Balzarini, Jan,McGuigan, Christopher
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experimental part
p. 5520 - 5530
(2010/02/28)
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- Naphthyl phosphoramidate derivatives of BVdU as potential anticancer agents: Design, synthesis and biological evaluation
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The phosphoramidate technology we have developed has been recently applied to BVdU, leading to NB1011 (NewBiotics Inc., California), a novel potential anticancer compound recently entered into phase 2 of the clinical trials for colon cancer. We report in
- Congiatu,McGuigan,Jiang,Davies,Mason
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p. 485 - 489
(2008/02/01)
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