- Fluorine substituted adenosines as probes of nucleobase protonation in functional RNAs
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Ionized nucleobases are required for folding, conformational switching, or catalysis in a number of functional RNAs. A common strategy to study these sites employs nucleoside analogues with perturbed pKa, but the interpretation of these studies
- Suydam, Ian T.,Strobel, Scott A.
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Read Online
- COMPOUNDS ACTIVE TOWARDS NUCLEAR RECEPTORS
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Disclosed are compounds active towards nuclear receptors, pharmaceutical compositions containing the compounds and use of the compounds in therapy.
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Page/Page column 124
(2021/10/11)
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- SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5
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The disclosure is directed to methods of treating disease using compounds of Formula (I).
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Paragraph 0251
(2020/10/20)
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- Synthesis and anti-HBV activity of carbocyclic nucleoside hybrids with salient features of entecavir and aristeromycin
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Modified carbocyclic nucleosides (4a-g) constituting 7-deazapurine, 4′-methyl, exocyclic double bond and 2′,3′-hydroxy were synthesized. NOE and X-ray studies of4cconfirmed the α-configuration of 4′-methyl. The anti-HBV assay demonstrated4e(IC50/sub
- Baba, Masanori,Bal, Chandralata,Jha, Ashok Kumar,Neeladri, Seshubabu,Pallaka, Renuka Sivasankar,Samunuri, Ramakrishnamraju,Toyama, Masaaki
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p. 597 - 601
(2020/06/08)
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- CYCLIC DINUCLEOTIDES AS STING AGONISTS
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Disclosed are compounds, compositions and methods for treating of diseases, syndromes, or disorders that are affected by the modulation of STING. Such compounds are represented by Formula (I) as follows: wherein B2,X2, R2a, R2b, R2c, Z-M-Y, Y1-M1Z1, B1, X1, R1a, R1b, R1c are as defined herein.
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Page/Page column 288-290
(2019/07/19)
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- Selective Inhibitors Of Protein Arginine Methyltransferase 5 (PRMT5)
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The disclosure is directed to compounds of Formula I Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.
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Paragraph 0282; 0283
(2019/02/24)
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- SUBSTITUTED NUCLEOSIDE DERIVATIVES USEFUL AS ANTICANCER AGENTS
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Compounds of the general formula (I): processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
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Paragraph 0310; 0311
(2016/09/26)
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- New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms
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A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms.
- Spurr, Sophie S.,Bayle, Elliott D.,Yu, Wenyu,Li, Fengling,Tempel, Wolfram,Vedadi, Masoud,Schapira, Matthieu,Fish, Paul V.
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supporting information
p. 4518 - 4522
(2016/08/24)
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- 4'-SUBSTITUTED NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Provided is 4'-substituted nucleoside derivatives of Formula I and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.
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- Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists
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Herein we describe the discovery, optimization, and structure-activity relationships of novel potent pyrrolopyrimidine Nav1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Nav1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts.
- Chakka, Nagasree,Bregman, Howie,Du, Bingfan,Nguyen, Hanh Nho,Buchanan, John L.,Feric, Elma,Ligutti, Joseph,Liu, Dong,McDermott, Jeff S.,Zou, Anruo,McDonough, Stefan I.,Dimauro, Erin F.
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scheme or table
p. 2052 - 2062
(2012/04/17)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Page/Page column 81
(2012/05/21)
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- Structure based medicinal chemistry approach to develop 4-methyl-7-deazaadenine carbocyclic nucleosides as anti-HCV agent
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The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure-activity relationships of previously discovered molecules (types I, II, III) were analyz
- Thiyagarajan, Anandarajan,Salim, Mohammed T.A.,Balaraju, Tuniki,Bal, Chandralata,Baba, Masanori,Sharon, Ashoke
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p. 7742 - 7747
(2013/02/22)
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- NOVEL PYRROLOY2,3-d¨PYRIMIDINE COMPOUND
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Disclosed is a novel pyrrolo[2,3-d]pyrimidine compound represented by formula [I] or a pharmacologically acceptable salt thereof, which has a GPR119 receptor agonistic activity and is useful for a pharmaceutical. In formula [I], E represents a group repre
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Page/Page column 54
(2011/12/12)
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- COMPOUNDS AND METHODS
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Disclosed are compounds having the Formula (I), wherein X, Y, Z, R1, R2 and R3 are as defined herein, and methods of making and using the same.
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Page/Page column 67
(2011/12/14)
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- CHEMICAL COMPOUNDS, COMPOSITIONS AND METHODS FOR KINASE MODULATION
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Chemical compounds that modulate kinase activity, including PI3 kinase activity, and chemical compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Page/Page column 111
(2011/12/04)
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- Synthesis and anti-HCV activity of a new 2′-deoxy-2′-fluoro- 2′-C-methyl nucleoside analogue
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2′-Deoxy-2′-fluoro-2′-C-methyl nucleoside analogue 4 was designed and synthesized. Initial biological studies indicated that this compound showed promising activity against HCV replication.
- Hu, Weidong,Wang, Ping'An,Song, Chuanjun,Pan, Zhenliang,Wang, Qiang,Guo, Xiaohe,Yu, Xuejun,Shen, Zhenhua,Wang, Shuyang,Chang, Junbiao
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scheme or table
p. 7297 - 7298
(2011/02/21)
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- Inhibition of dengue virus RNA synthesis by an adenosine nucleoside
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We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin- 7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC50) and cytotoxic concentration (CC50) values of 0.7 μM and >100 μM, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that 14C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis. Copyright
- Chen, Yen-Liang,Yin, Zheng,Duraiswamy, Jeyaraj,Schul, Wouter,Lim, Chin Chin,Liu, Boping,Xu, Hao Ying,Qing, Min,Yip, Andy,Wang, Gang,Chan, Wai Ling,Tan, Hui Pen,Lo, Melissa,Liung, Sarah,Kondreddi, Ravinder Reddy,Rao, Ranga,Gu, Helen,He, Handan,Keller, Thomas H.,Shi, Pei-Yong
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body text
p. 2932 - 2939
(2011/10/09)
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- P70 S6 KINASE INHIBITORS
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The present invention provides p70 S6 kinase inhibitors of the formula: pharmaceutical formulations comprising them, and methods for their use.
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Page/Page column 36
(2009/01/20)
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- Inhibitors of E1 activating enzymes
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This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.
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Page/Page column 57
(2010/11/28)
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- METHODS FOR THE PREPARATION OF 5-FLUORO-PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS
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5-fluoro-pyrrolo[2,3-d]pyrimidine and 5-fluoro-pyrrolo[2,3-d]pyrimidine nucleoside compounds and methods for their preparation are disclosed.
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Page/Page column 12
(2008/06/13)
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- Synthesis and Biological Activity of 5-Fluorotubercidin
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The electrophilic fluorination of 4-chloropyrrolo[2,3-d]pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4-chloro-5-fluoropyrrolo[2,3-d]-pyrimidine (2) using Selectfluor. This transformation proceeded via the 4-chloro-5,6-dihydro-5
- Wang, Xiaojing,Seth, Punit P.,Ranken, Ray,Swayze, Eric E.,Migawa, Michael T.
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p. 161 - 170
(2007/10/03)
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- ANTI-VIRAL 7-DEAZA D-NUCLEOSIDES AND USES THEREOF
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The present invention relates generally to anti-viral compounds, particularly anti-viral 7-deaza D-nucleosides and analogues, or derivatives thereof. The invention also relates to the use of such compounds to treat or prevent hepatitis B virus (HBV) infec
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- Structure - activity relationship of heterobase-modified 2′-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication
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Hepatitis C virus infection constitutes a significant health problem in need of more effective therapies. We have recently identified 2′-C-methyladenosine and 2′-C-methylguanosine as potent nucleoside inhibitors of HCV RNA replication in vitro. However, both of these compounds suffered from significant limitations. 2′-C-Methyladenosine was found to be susceptible to enzymatic conversions by adenosine deaminase and purine nucleoside phosphorylase, and it displayed limited oral bioavailability in the rat. 2′-C-Methylguanosine, on the other hand, was neither efficiently taken up in cells nor phosphorylated well. As part of an attempt to address these limitations, we now report upon the synthesis and evaluation of a series of heterobase-modified 2′-C-methyl ribonucleosides. The structure-activity relationship within this series of nucleosides reveals 4-amino-7-(2-C-methyl- β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C- methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as potent and noncytotoxic inhibitors of HCV RNA replication. Both 4-amino-7-(2-C-methyl- β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C- methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine display improved enzymatic stability profiles as compared to that of 2′-C-methyladenosine. Consistent with these observations, the most potent compound, 4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine ribonucleoside, is orally bioavailable in the rat. Together, the potency of the 2′-C-methyl-4-amino- pyrrolo[2,3-d]pyrimidine ribonucleosides and their improved pharmacokinetic properties relative to that of 2′-C-methyladenosine suggests that this class of compounds may have clinical utility.
- Eldrup, Anne B.,Prhavc, Marija,Brooks, Jennifer,Bhat, Balkrishen,Prakash, Thazha P.,Song, Quanlai,Bera, Sanjib,Bhat, Neelima,Dande, Prasad,Cook, P. Dan,Bennett, C. Frank,Carroll, Steven S.,Ball, Richard G.,Bosserman, Michele,Burlein, Christine,Colwell, Lawrence F.,Fay, John F.,Flores, Osvaldo A.,Getty, Krista,LaFemina, Robert L.,Leone, Joseph,MacCoss, Malcolm,McMasters, Daniel R.,Tomassini, Joanne E.,Von Langen, Derek,Wolanski, Bohdan,Olsen, David B.
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p. 5284 - 5297
(2007/10/03)
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