- Synthesis of [2-14C,5-3H]cytosine and [2-14C,5-3H]uracil via bromination and catalytic bromine-tritium gas exchange
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In micro-scale experiments, [2-14C,5-3H]cytosine and [2-14C,5-3H]uracil were synthesized via bromination and catalytic Br-3H exchange reaction with the use of [2-14C]cytosine and -uracil and tritium gas. The double labelling percentages of these products were 70 and 26, respectively. It was assumed that [2-14C,5-Br]uracil was subjected to reaction with hydrogen atom originally adsorbed on a palladium catalyst. This is to a lesser extent valid for [2-14C,5-Br]cytosine. The percentages of 3H labelling at 5 position of pyrimidine ring of cytosine and uracil were proved to be 96 and 73, respectively. For the analysis and purification of products, the HPLC eluting conditions using C18 reverse column and NaH2PO4 aqueous solution or H2O/methanol mixture as eluent were studied. Unreacted tritium gas was recovered with the use of adsorbents such as active charcoal and Zr-V-Fe getter.
- Asano,Kiritani
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- Synthesis, structure and rearrangement of iodinated imidazo[1,2-c]pyrimidine-5(6H)-ones derived from cytosine
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We describe mild and selective iodination of various 8-substituted imidazo[1,2-c]pyrimidine-5(6H)-ones (ethenocytosines). Starting ethenocytosines were obtained by cyclization of 5-halogenocytosines with chloroacetaldehyde or by subsequent Suzuki-Miyaura
- Jansa, Josef,Ly?ka, Antonín,R??i?ka, Ale?,Grepl, Martin,Vaně?ek, Jan
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- Exploiting the 7-methylimidazo[1,5-a]pyrazin-8(7H)-one scaffold for the development of novel chemical inhibitors for Bromodomain and Extraterminal Domain (BET) family
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The bromodomain and extraterminal (BET) family of proteins play a crucial role in promoting gene expression of critical oncogenes. Novel BET bromodomain inhibitors with excellent potency, drug metabolism and pharmacokinetics (DMPK) properties were in strong need for development. We reported a series of potential BET inhibitors through incorporation of imidazole into pyridine scaffold. Among them, a novel BET inhibitor with 7-methylimidazo[1,5-a]pyrazin-8(7H)-one core, compound 28, was considered to be the most promising for in-depth study. Compound 28 exhibited excellent BRD4-inhibitory activity with IC50 value of 33 nM and anti-proliferation potency with IC50 value of 110 nM in HL-60 (human promyelocytic leukemia) cancer cell lines. Western Blot indicated that compound 28 can effectively trigger apoptosis in BxPc3 cells by modulating the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 28 has merely potential for leukemia treatment.
- Yang, Yifei,Chen, Pan,Zhao, Leilei,Zhang, Fangqing,Zhang, Bing,Xu, Changliang,Zhang, Huibin,Zhou, Jinpei
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- IMIDAZO[1,2-C]PYRIMIDINE DERIVATIVES AS PRC2 INHIBITORS FOR TREATING CANCER
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Disclosed are compounds that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, disclosed are compounds of Formula (I) and pharmaceutical compositions thereof, and methods of using the compounds and pharmaceutical compositions in, for example, methods of treating cancer.
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Paragraph 0163-0164
(2020/12/29)
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- CYTOSINE-BASED TET ENZYME INHIBITORS
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Provided herein, in some embodiments, are cytosine analogs, compositions comprising cytosine analogs, and methods of use for inhibiting a Ten-eleven translocation (TET) enzyme.
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Paragraph 0174; 0175
(2020/11/24)
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- CYTOSINE-BASED TET ENZYME INHIBITORS
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Provided herein, in some embodiments, are cytosine analogs, compositions comprising cytosine analogs, and methods of use for inhibiting a Ten-eleven translocation (TET) enzyme.
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Page/Page column 51
(2020/10/20)
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- PRC2 INHIBITORS
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The present invention relates to compounds that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention. (Formula (I))
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Paragraph 0145; 0148-0150
(2019/08/26)
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- Cytosine-Based TET Enzyme Inhibitors
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DNA methylation is known as the prima donna epigenetic mark for its critical role in regulating local gene transcription. Changes in the landscape of DNA methylation across the genome occur during cellular transition, such as differentiation and altered neuronal plasticity, and become dysregulated in disease states such as cancer. The TET family of enzymes is known to be responsible for catalyzing the reverse process that is DNA demethylation by recognizing 5-methylcytosine and oxidizing the methyl group via an Fe(II)/alpha-ketoglutarate-dependent mechanism. Here, we describe the design, synthesis, and evaluation of novel cytosine-based TET enzyme inhibitors, a class of small molecule probes previously underdeveloped but broadly desired in the field of epigenetics. We identify a promising cytosine-based lead compound, Bobcat339, that has mid-μM inhibitor activity against TET1 and TET2, but does not inhibit the DNA methyltransferase, DNMT3a. In silico modeling of the TET enzyme active site is used to rationalize the activity of Bobcat339 and other cytosine-based inhibitors. These new molecular tools will be useful to the field of epigenetics and serve as a starting point for new therapeutics that target DNA methylation and gene transcription.
- Chua, Gabriella N. L.,Wassarman, Kelly L.,Sun, Haoyu,Alp, Joseph A.,Jarczyk, Emma I.,Kuzio, Nathanael J.,Bennett, Michael J.,Malachowsky, Beth G.,Kruse, Martin,Kennedy, Andrew J.
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supporting information
p. 180 - 185
(2019/02/24)
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- Dehalogenation of Halogenated Nucleobases and Nucleosides by Organoselenium Compounds
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Halogenated nucleosides, such as 5-iodo-2′-deoxyuridine and 5-iodo-2′-deoxycytidine, are incorporated into the DNA of replicating cells to facilitate DNA single-strand breaks and intra- or interstrand crosslinks upon UV irradiation. In this work, it is shown that the naphthyl-based organoselenium compounds can mediate the dehalogenation of halogenated pyrimidine-based nucleosides, such as 5-X-2′-deoxyuridine and 5-X-2′-deoxycytidine (X=Br or I). The rate of deiodination was found to be significantly higher than that of the debromination for both nucleosides. Furthermore, the deiodination of iodo-cytidines was found to be faster than that of iodo-uridines. The initial rates of the deiodinations of 5-iodocytosine and 5-iodouracil indicated that the nature of the sugar moiety influences the kinetics of the deiodination. For both the nucleobases and nucleosides, the deiodination and debromination reactions follow a halogen-bond-mediated and addition/elimination pathway, respectively.
- Mondal, Santanu,Mugesh, Govindasamy
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p. 1773 - 1780
(2019/01/10)
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- A 5-fluorocytosine preparation method
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The invention discloses a preparation method of 5-flucytosine. The method comprises the following steps of: 1) cytosine and a halogenating reagent perform halogenating reaction in an organic solvent at 0-80 DEG C to prepare an intermediate (I), 2) the intermediate (I) reacts with an amino protecting agent at 0-120 DEG C to prepare an intermediate (II), and 3) the intermediate (II) and a fluoro reagent perform fluoro reaction in a polar aprotic solvent or hydrogen fluoride at 70-200 DEG C to prepare an intermediate (III), and the intermediate (III) directly performs amino deprotecting reaction, and is separated and purified to prepare 5-flucytosine. According to the method, a process route is reasonable, the product yield is high, the quality is good, the production safety of the fluoro reagent is high, and the method is simple to operate and suitable for industrial production.
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Paragraph 0023-0025; 0031-0032; 0037; 0038
(2017/01/17)
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- Xanthine oxidase-activated prodrugs of thymidine phosphorylase inhibitors
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Thymidine phosphorylase (TP) is over-expressed in various tumour types and plays an important role in tumour angiogenesis, growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP, therefore, inhibitors of TP are of significant interest in cancer chemotherapy. A series of xanthine oxidase (XO) activated prodrugs of known inhibitors of TP have been designed and synthesized with the ultimate intent of improving tumour selectivity and pharmacokinetic characteristics. These prodrugs were not inhibitors of TP, but were selectively oxidized by XO at C-2 and/or C-4 of the uracil ring moiety to generate the desired TP inhibitor. Molecular modelling of both the TP inhibitors and XO-activated prodrugs rationalized their binding in the active site of the human TP crystal structure.
- Reigan, Philip,Gbaj, Abdul,Stratford, Ian J.,Bryce, Richard A.,Freeman, Sally
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p. 1248 - 1260
(2008/09/21)
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- Mild regioselective monobromination of activated aromatics and heteroaromatics with N-bromosuccinimide in tetrabutylammonium bromide
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Highly regioselective nuclear bromination of activated aromatic and heteroaromatic compounds has been accomplished using N-bromosuccinimide in tetrabutylammonium bromide. Pre-dominant para-selective monobromination of activated aromatics such as phenols and anilines, rate acceleration of bromination for moderately activated and less reactive substrates on addition of acidic montmorillonite K-10 clay, with or without microwave assistance, are the notable features of this protocol.
- Ganguly, Nemai C.,De, Prithwiraj,Dutta, Sanjoy
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p. 1103 - 1108
(2007/10/03)
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- Synthesis and enzymatic evaluation of xanthine oxidase-activated prodrugs based on inhibitors of thymidine phosphorylase
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A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase are described. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor. The scheme shows the prodrug of TPI. A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase has been designed and synthesised to introduce tumour selectivity. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor.
- Reigan, Philip,Gbaj, Abdul,Chinje, Edwin,Stratford, Ian J.,Douglas, Kenneth T.,Freeman, Sally
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p. 5247 - 5250
(2007/10/03)
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- In-cell Indirect Electrochemical Halogenation of Pyrimidine Bases and their Nucleosides to 5-Haloderivatives
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Reaction of anodically generated "halonium" species (LiX or Bu4NX, LiClO4, MeCN, Pt/Pt; I2, LiClO4, MeCN) with pyrimidine bases and their nucleosides leads to 5-halo compounds in good yields.
- Palmisano, G.,Danieli, B.,Santagostino, M.,Vodopivec, B.,Fiori, G.
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p. 7779 - 7782
(2007/10/02)
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- Chloroperoxidase Catalyzed Halogenation of Pyrimidine Bases
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Treatment of uracil or cytosine with H2O2 and potassium halides in the presence of chloroperoxidase in potassium phosphate buffer solution at pH 3.0 resulted in halogenation of the substrates, whereas no reaction occured on thymine by a similar treatment.
- Itahara, Toshio,Ide, Naoko
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p. 2311 - 2312
(2007/10/02)
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- Nucleoside process
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Process for producing 1-halo-2-deoxy-2-fluoroarabinofuranoside derivatives bearing protective ester groups from 1,3,5-tri-O-acylribofuranose; the 1-halo compounds are intermediates in the synthesis of therapeutically active nucleosidic compounds.
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- Mechanisms of Bromination of Uracil Derivatives. 6. Cytosine and N-Substituted Derivatives
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The reactions of bromine with cytosine, 1-methylcytosine, cytidine, and 3-methylcytosine in acidic aqueous sloutions have been studied.Initially adducts (5-bromo-5,6-dihydro-6-hydroxycytosines) are produced which are clearly observable by proton NMR, albeit in their protonated forms in the acidic media used.In time the adducts undergo elimination of water to give substitution products, 5-bromocytosines.Kinetic measurements of the initial reaction in the pH range 0-5 are consistent with the adducts resulting from rate-determining attack of bromine in the free base form of the cytosine substrates followed by capture of the cation so produced by water.An alternative mechanism involving first hydration and then bromine attack can be ruled out.
- Tee, Oswald S.,Kornblatt, Mary Judith,Berks, Charles G.
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p. 1018 - 1023
(2007/10/02)
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