- Structural Effects in Phosphates. 1. Comparison of 4-Nitrophenyl 1-Naphthyl and 4-Nitrophenyl Quinolin-8-yl Phosphates
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Crystal and molecular structures of quinolin-8-yl bis(p-nitrophenyl) (4), quinolin-8-yl p-nitrophenyl (4a), and 1-naphthyl bis(p-nitrophenyl) phosphates (5) have been determined and compared.In 4 the donor-acceptor nitrogen-phosphorus interactions change the geometry of the molecule from tetrahedral to quasi-tbp, so the structure can be considered as an "early stage" of the intramolecular displacement of the PNPO group.In 4a this interaction is replaced by intramolecular N:H:O hydrogen bonding.The intramolecular nonbonded potential energies of 4 and 5 were calculated, and the minimum-energy conformations obtained were compared with those determined by X-ray diffraction.The results of calculations confirm the observed differences in the intramolecular interactions operating in 4 and 5.The mass spectra of 4 and 5 reveal a dramatic difference between these two phosphates with respect to the fragmentation involving the expulsion of the p-nitrophenoxy radical and the formation of the corresponding phosphorylium ion by the nitrogen atom.Rate measurements for the base-catalyzed hydrolysis of the P-OPNP linkage show that 4 is not significantly more reactive than 5 and provide no evidence for the intramolecular nucleophilic catalysis in the hydrolysis of 4.
- Bond, D. R.,Modro, T. A.,Nassimbeni, L. R.
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Read Online
- 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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Read Online
- Prodrug compound and application ofprodrug compound in treatment of cancer
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The present invention provides a compound indicated by a formula (I), pharmaceutically acceptable salts or esters thereof, a pharmaceutical composition of the compound, and application of the compoundand the pharmaceutical composition in the inhibition or regulation of the activity of tyrosine kinase and treating disease symptoms or symptoms including cancer mediated by tyrosine kinase.
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Paragraph 0136-0137; 0144-0145
(2021/03/06)
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- Deuterated compound and application thereof in treatment of cancer
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The present invention relates to a deuterated compound and application thereof in the treatment of cancer. Specifically, the present invention provides the compound of formula (I) and pharmaceuticallyacceptable salt or ester thereof, and a pharmaceutical composition thereof. The compound and the pharmaceutical composition are used for inhibiting or regulating the activity of tyrosine kinase and treating disease symptoms or symptoms including cancer mediated by tyrosine kinase.
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Paragraph 0139-0140
(2021/03/06)
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- PRODRUGS OF THE TYROSINE KINASE INHIBITOR FOR TREATING CANCER
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There are provided compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, useful for inhibition or modulation of the activity of tyrosine kinases and treatment of disease states or conditions mediated by tyrosine kinases, including cancers. (I)
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Paragraph 0097-0098; 00105-00106
(2021/03/05)
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- PRODRUGS OF A CDK INHIBITOR FOR TREATING CANCERS
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There are provided compounds of Formula I, and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, used for inhibition or modulation of the activity of cyclin dependent kinases (CDK) and/or glycogen synthase kinase-3 (GSK-3), for the treatment of disease states or conditions mediated by cyclin dependent kinases and/or glycogen synthase kinase-3, including cancers. (I)
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Paragraph 00129
(2020/11/03)
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- 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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p. 200 - 208
(2019/03/05)
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- 4'-FLUORO-2'-METHYL SUBSTITUTED NUCLEOSIDE DERIVATIVES AS INHIBITORS OF HCV RNA REPLICATION
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Cytidine nucleoside analogues of Formula I, wherein the variables are as described herein, in combination with uridine nucleoside analogues of Formula II, wherein the variables are as described herein, produce a synergistic effect on the inhibition of HCV
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Paragraph 0163-0164
(2019/04/16)
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- PHOSPHORODIAMIDATES AND OTHER PHOSPHORUS DERIVATIVES OF FINGOLIMOD AND RELATED S1 P RECEPTOR MODULATORS
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Compounds of general formula (I): (Formula I)) wherein R1, Q, R3, R4, R5, R6, R7 and Ar1 are as defined herein are inhibitors of class I histone deacetylases and are of use in th
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Page/Page column 30
(2019/04/26)
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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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- 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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p. 551 - 565
(2017/12/28)
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- Reactivity of Ferrocenyl Phosphates Bearing (Hetero-)Aromatics and [3]Ferrocenophanes toward Anionic Phospho-Fries Rearrangements
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The temperature-dependent behavior within anionic phospho-Fries rearrangements (apFr) of P(O)(OFc)n(EAr)3-n (Fc = Fe(η5-C5H5)(η5-C5H4); E = O; Ar = phenyl, naphthyls, (R)-BINOL, [3]ferrocenophanyl; E = N, 1H-pyrrolyl, 1H-indolyl, 9H-carbazolyl; n = 1-3) is reported. While Fc undergoes one, the Ph-based apFr depends on temperature. First, the aryls are lithiated and rearranged, followed by Fc and N-heterocycles. Addition of Me2SO4 thus gave methylated Fc, contrary to non-organometallic aromatics giving mixtures of HO and MeO derivatives. The (R)-BINOL Fc phosphate gave Fc-rearranged phosphonate in 91% de. Exchanging O- with N-aliphatics prevented apFr, due to higher electron density at P. Also 1,2-N→C migrations were observed. X-ray analysis confirms 1D H bridge bonds for OH and NH derivatives. The differences in reactivity between N-aliphatic and N-aromatic phosphoramidates were verified by electrochemistry. The redox potentials revealed lower values for the electron-rich aliphatics, showing no apFr, preventing a nucleophilic attack at P after lithiation. Redox separations for multiple Fc molecules are based on electrostatic interactions.
- Korb, Marcus,Lehrich, Steve W.,Lang, Heinrich
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p. 3102 - 3124
(2017/03/23)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Picornavirus and/or Flaviviridae infection with one or more nucleosides, nucleotides and nucleotide analogs.
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Paragraph 0834; 0995; 1000
(2015/04/21)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.
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Paragraph 0749; 0755
(2016/03/08)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a Filoviridae virus infection with one or more nucleosides and/or nucleotide analogs.
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Paragraph 0699; 0705
(2016/03/11)
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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 0090
(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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p. 1531 - 1542
(2014/03/21)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.
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Paragraph 0441
(2014/07/08)
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- Palladium-catalyzed ortho-alkenylation of aryl hydrogen phosphates using a new mono-phosphoric acid directing group
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A highly efficient Pd-catalyzed ortho-alkenylation is reported using a mono-phosphoric acid-directing group for the first time. This phosphoric acid-directing group is successfully utilized for the synthesis of various alkenylated products and offers a new approach to transition-metal-catalyzed C-H activation. The Royal Society of Chemistry 2013.
- Chan, Li Yan,Kim, Sunggak,Ryu, Taekyu,Lee, Phil Ho
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supporting information
p. 4682 - 4684
(2013/06/04)
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- 2',4'-DIFLUORO-2'-METHYL SUBSTITUTED NUCLEOSIDE DERIVATIVES AS INHIBITORS OF HCV RNA REPLICATION
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The present disclosure relates to compounds of Formula (I): Also disclosed are pharmaceutical compositions comprising compounds of Formula (I), methods of using the compounds of Formula (I) and/or compositions comprising the compounds of Formula (I) for the treatment of HCV.
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Page/Page column 35
(2013/07/05)
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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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Page/Page column 44
(2013/07/05)
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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 24
(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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scheme or table
p. 35 - 43
(2012/07/28)
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- PHOSPHORAMIDATE DERIVATIVES OF NUCLEOSIDES
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Compounds of formula I : including any possible stereoisomers thereof, wherein: R1 is hydrogen, -C(=O)R6 or -C(=O)CHR7-NH2; R2 is hydrogen; or C1-C6alkyl or phenyl, either of whi
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Page/Page column 18
(2011/04/25)
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- Phosphoramidate protides of the anticancer agent fudr successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside
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The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependen
- McGuigan, Christopher,Murziani, Paola,Slusarczyk, Magdalena,Gonczy, Blanka,Vande Voorde, Johan,Liekens, Sandra,Balzarini, Jan
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scheme or table
p. 7247 - 7258
(2011/12/21)
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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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- Application of the phosphoramidate ProTide approach to the antiviral drug ribavirin
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Ribavirin is a nucleoside analogue with broad antiviral activity. Here we report the synthesis and biological evaluation of novel ribavirin ProTides designed to deliver the bioactive ribavirin monophosphate into cells. Some of the compounds display activity similar to the parent nucleoside against a range of viruses. Enzymatic, cell lysate and preliminary modeling studies have been performed to investigate the lack of enhancement of potency by the ProTides, and these indicate a failure at the final, amino acid cleavage step in the ProTide activation process, leading to inefficient release of the nucleoside monophosphate.
- Derudas, Marco,Brancale, Andrea,Naesens, Lieve,Neyts, Johan,Balzarini, Jan,McGuigan, Christopher
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experimental part
p. 2748 - 2755
(2010/06/19)
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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 84-85
(2010/08/04)
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- Phosphoramidate Derivatives of Nucleosides
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Compounds of formula I : R1 is hydrogen, C1-C4alkyl, OH, C1-C4alkoxy; R2 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently selected from halo, C1-C
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Page/Page column 8
(2010/04/24)
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- Nucleoside Aryl Phosphoramidates for the Treatment of RNA-Dependent RNA Viral Infection
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The present invention provides nucleoside aryl phosphoramidates of structural formula (I) which are precursors to inhibitors of RNA-dependent RNA viral polymerase. These compounds are precursors to inhibitors of RNA-dependent RNA viral replication and are
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Page/Page column 13
(2010/09/18)
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- Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus
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We herein report a novel double pro-drug approach applied to the anti-HCV agent 2′-β-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanin
- McGuigan, Christopher,Madela, Karolina,Aljarah, Mohamed,Gilles, Arnaud,Brancale, Andrea,Zonta, Nicola,Chamberlain, Stanley,Vernachio, John,Hutchins, Jeff,Hall, Andrea,Ames, Brenda,Gorovits, Elena,Ganguly, Babita,Kolykhalov, Alexander,Wang, Jin,Muhammad, Jerry,Patti, Joseph M.,Henson, Geoffrey
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body text
p. 4850 - 4854
(2010/10/18)
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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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Page/Page column 18-19
(2010/06/22)
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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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- Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2′-deoxyzebularine
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We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2′-deoxyzebularine 5′-triphosphate (dZTP). Because 2′-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5′-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma cells.
- Yoo, Christine B.,Valente, Rocco,Congiatu, Costantino,Gavazza, Federica,Angel, Annette,Siddiqui, Maqbool A.,Jones, Peter A.,McGuigan, Christopher,Marquez, Victor E.
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experimental part
p. 7593 - 7601
(2009/12/07)
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- Antiviral phosphoramidates
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The invention provides novel nucleoside compounds of formula I wherein R1, R2a, R2b, R3, R4, R5, R6, R8a, R9 and R10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,
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Page/Page column 18
(2008/06/13)
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- Application of the phosphoramidate ProTide approach to 4′- azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside
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We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4′-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4′-Azidouridine did not inhibit HCV, although 4′-azidocyti
- Perrone, Plinio,Luoni, Giovanna M.,Kelleher, Mary Rose,Daverio, Felice,Angell, Annette,Mulready, Sinead,Congiatu, Costantino,Rajyaguru, Sonal,Martin, Joseph A.,Levêque, Vincent,Le Pogam, Sophie,Najera, Isabel,Klumpp, Klaus,Smith, David B.,McGuigan, Christopher
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p. 1840 - 1849
(2008/02/04)
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- Novel potential anticancer naphthyl phosphoramidates of BVdU: Separation of diastereoisomers and assignment of the absolute configuration of the phosphorus center
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We have previously reported our SAR optimization of the anticancer agent thymectacin. Tuning of the parent ProTide structure initially involved the amino acid and, subsequently, the aromatic masking group on the phosphate moiety. Herein, derivatives beari
- Congiatu, Costantino,Brancale, Andrea,Mason, Malcolm D.,Jiang, Wen G.,McGuigan, Christopher
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p. 452 - 455
(2007/10/03)
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- Synthesis and metabolism of naphthyl substituted phosphoramidate derivatives of stavudine
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The synthesis of naphthylphosphoramidate derivatives of stavudine was achieved using a four-step procedure. The derivatives were subjected to several different enzymes including lipase, esterase, Subtilisin Carlsberg, and Carica papaya, and their hydrolysis rates were determined. Based on the rates of hydrolysis, we were able to differentiate between the chiralities at the phosphorus center of the phosphoramidate compounds. In addition, lipase was found to distinguish between both α and β forms of the compounds. The superior chiral selectivity shown by lipase toward the naphthyl substituted phosphoramidate derivatives is attributed to the restrictive binding pocket of the lipase.
- Venkatachalam,Qazi,Uckun
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p. 5161 - 5177
(2008/02/05)
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- Synthesis of some new chiral bifunctional o-hydroxyarylphosphonodiamides and their application as ligands in Ti(IV) complex catalyzed asymmetric silylcyanation of aromatic aldehydes
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Some new chiral bifunctional o-hydroxyarylphosphonodiamides were synthesized starting from (+)-cis-1,2,2-trimethylcyclopentane-1,3-diamine and the absolute configuration of the phosphorus atom was determined by X-ray diffraction analysis. Excellent enantioselectivity (up to 98% ee) was achieved in asymmetric silylcyanation of aromatic aldehydes using a chiral titanium complex formed in situ from Ti(OiPr)4 and o-hydroxyarylphosphonodiamide as the catalyst. Graphical Abstract.
- He, Ke,Zhou, Zhenghong,Wang, Lixin,Li, Kangying,Zhao, Guofeng,Zhou, Qilin,Tang, Chuchi
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p. 10505 - 10513
(2007/10/03)
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