- Synthesis of 2'-methylene-substituted 5-azapyrimidine, 6-azapyrimidine, and 3-deazaguanine nucleoside analogues as potential antitumor/antiviral agents
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2'-Deoxy-2'-methylene-6-azauridine (5) and 2'-deoxy-2'-methylene-6- azacytidine (8) have been synthesized via a multi-step procedure from 6- azauridine. 2'-Deoxy-2'-methylene-5-azacytidine (14a) and 2'-deoxy-2'- methylene-3-deazaguanosine (19a) and their corresponding α-anomers (14b and 19b) have been synthesized by the transglycosylation of 3',5'-O-(1,1,3,3- tetraisopropyldisiloxane-1,3-diyl)-2'-deoxy-2'-methyleneuridine (12) with silylated 5-azacytosine and silylated N2-palmitoyl-3-deazaguanine, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by separation of the isomers and deprotection of the blocking groups. These compounds were tested for cytotoxicity against B16F10, L1210, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1, HSV-1, and HSV-2.
- Liu, Mao-Chin,Luo, Mei-Zhen,Mozdziesz, Diane E.,Lin, Tai-Shun,Dutschman, Ginger E.,Cheng, Yung-Chi,Sartorelli, Alan C.
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- Preparation method of medical intermediate 2 ', 3', 5 '-triacetyl azacitidine
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The invention discloses a preparation method of a medical intermediate 2 ', 3', 5 '-triacetyl azacitidine, which comprises the following steps: adding a proper amount of 5-azacytosine and hexamethyldisilazane into a reaction flask, adding a catalyst, and reacting to obtain a silanization protection substance; dissolving the silanization protection substance in dichloromethane, adding 2 ', 3', 5 '-triacetyl uridine and a proper amount of Lewis acid, and carrying out a base exchange reaction to obtain 2', 3 ', 5'-triacetyl azacitidine; the preparation method of the medical intermediate 2 ', 3', 5 '-triacetyl azacitidine has the advantages of easily available raw materials, low cost, simple preparation process, no dangerous steps such as high temperature and high pressure, relatively low requirements on equipment, mild reaction, high safety, high product yield, high purity, less three wastes, no environmental pollution and suitability for industrial production.
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Paragraph 0028; 0038-0039; 0041-0042; 0044-0045
(2021/08/06)
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- 5-azacytidine compound and preparation method thereof
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The invention relates to a 5-azacytidine compound and a preparation method thereof. The structural formula of the 5-azacytidine compound is shown in a formula I (shown in the specification). The compound is obtained from 5-azacytosine as a starting material by upper protection, condensation, deprotection, recondensation and a deprotection rection. Through studies of related substances, recognitionand control of an impurity profile in the 5-azacytidine compound are strengthened, the quality of a finished product is advantageously controlled, and a guarantee is provided for the safety of clinical medication. The synthesis process is simple in operation, good in yield and purity, and is environment friendly.
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Paragraph 0049-0052
(2020/02/19)
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- 2-deoxy-D-ribose derivative
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The invention belongs to the field of medicine synthesis, and provides a 2-deoxy-D-ribose derivative (III). When the derivative (III) is used for preparing decitabine, the stereoselectivity is good, and the yield is high. The invention provides a preparation method of the derivative. The preparation method comprises the following steps: step a, carrying out oxygen methylation on 1-position hydroxyl of 2-deoxy-D-ribose; and step b, protecting hydroxyl groups at positions 3 and 5, and further carrying out sulfonation on 1-position oxymethyl. The method is simple and convenient to operate, free of special equipment, good in product purity, high in yield and suitable for industrial production.
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Paragraph 0080-0081; 0083-0084
(2020/08/09)
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- Preparation method of decitabine intermediate
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The invention belongs to the field of pharmaceutical synthesis, and discloses a preparation method and a purification method of a decitabine intermediate (V). The preparation method comprises the following steps of enabling 2-deoxygenation-D-ribose derivative (III) and hexamethyldisilazane-activated 5-azacytosine (IV) to be subjected to a coupling reaction under the action of a catalyst to be purified to obtain the decitabine intermediate (V). The method is simple and convenient to operate, no silica gel column purification product is needed, and the method is suitable for industrial production.
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Paragraph 0018; 0050-0051; 0053-0055; 0057-0058; 0060-0061
(2020/07/24)
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- Preparation method of azacitidine (by machine translation)
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The invention belongs to the field, and belongs to the field of medicine synthesis. The preparation method comprises the following steps: 5 - aza cytidine and trimethylchlorosilane are reacted, and the azacitidine intermediate I is 70 - 80 °C dissolved, and 2 hours is reacted with 1 - chlorine -2, 3, 5 - three - O O-p-chlorobenzoyl - β-D - ribose under the catalysis of boron trifluoride. the reaction is finished, washed, dried, filtered and filtered, and the filtrate is distilled under reduced pressure to obtain the azacitidine intermediate II; and the method, the method comprises the following steps. The azacitidine intermediate II is purified by ammonia alcoholysis to obtain the azacitidine with high purity by purifying the crude azacitidine crude product. The method has the advantages of mild reaction conditions, short reaction time, high yield, and suitability for industrial production. (by machine translation)
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Paragraph 0024; 0025; 0028; 0029; 0032; 0033; 0036; 0037
(2019/10/01)
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- Method for preparing azacitidine by high-purity and low-calcination residue
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The invention relates to the field of a pharmaceutical synthesis technology, and discloses a method for synthesizing azacitidine. The method improves the quality and product purity of azacitidine, andthe reaction conditions are easy to control and reduce the production cost, and the method is suitable for industrial preparation.
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Paragraph 0014; 0043-0044; 0048-0049; 0053-0054; 0058-0059
(2019/10/01)
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- Preparation method of azacitidine
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The invention relates to a preparation method of azacitidine. According to the method, the azacitidine is prevented from making contact with water, degradation of the azacitidine is reduced, the operation is simple, and yield and purity are greatly increased. In addition, in the further purification process of the azacitidine, ethyl alcohol is used as a crystal transformation solvent, the cost isgreatly reduced, and the method is more suitable for industrial application.
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Paragraph 0026; 0027
(2019/02/19)
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- Synthesis and properties of cross-linkable DNA duplex using 4-amino-2-oxo-6-vinyl-1,3,5-triazine
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We synthesized the DNA oligonucleotide containing a new cross-linkable 4-amino-2-oxo-6-vinyltriazine (AOVT) nucleobase analogue (Et-AOVT) and evaluated these properties. Our results of the cross-link assay and thermal denaturing assay of duplexes containing AOVT demonstrated that the additional aza of AOVT has an impact on the duplex stability and crosslink properties. Our data suggests that the additional 5-aza of AOVT is involved in the hydrogen bonding with the complementary guanine, and this hydrogen bonding system successfully flipped the reactive vinyl group out to the major groove of the duplex demonstrating a new paradigm of a “cross-linkable duplex”.
- Yamada, Ken,Ishiyama, Shogo,Onizuka, Kazumitsu,Nagatsugi, Fumi
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p. 1424 - 1435
(2017/02/18)
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- Synthesis, Hydrolytic Stability, and Antileukemic Activity of Azacytidine Nucleoside Analogs
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New azacytidine nucleoside analogs with modified carbohydrate moieties were synthesized. Screening identified a highly active 2′-fluoro-containing azacytidine analog that could potentially be of interest as an agent for treating acute myelogenous leukemia and myelodysplastic syndrome.
- Bozhok,Kalinichenko,Kuz’mitskii,Golubeva
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p. 804 - 809
(2016/05/02)
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- A SITAR hamanaka process for the preparation of intermediates
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The invention discloses a preparation method of a decitabine intermediate compound 1-acetoxyl-2-deoxidized-3,5-bi-O-fluorene methyl cyslohexyl-D-ribofuranose. The structural formula of the compound is shown in img file='DDA0000455164900000011.TIF' wi='648' he='304'/, and the preparation method comprises the following steps: o-methylation of 2'-deoxidized-D-ribose 1-bit hydroxyl; b) protection of 3,5-bit hydroxyl; and c) acylation of 1-bit-O-methyl. The invention also discloses a method for preparing decitabine employing the intermediate as a raw material.
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Paragraph 0087; 0088
(2016/10/08)
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- A used with the industrial production method for the synthesis of
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The invention relates to a decitabine synthesis and industrial production method, which comprises the following steps of: using 2-Deoxy-D-ribose as a raw material, performing a reaction between the raw material and methanol to obtain glucoside, protecting 3,5-dihydroxy by the use of 9-fluorenylmethyloxycarbonyl, reacting with hydrogen chloride to obtain 1-chlorflurecol sugar, performing a reaction between 1-chlorflurecol sugar and silanized 5-azacytosine, carrying out deprotection, and refining to obtain decitabine. The invention is characterized in that stannic chloride is not required during the condensation reaction between 1-chlorflurecol sugar and silanized 5-azacytosine so as to avoid the problem of excessive contents of heavy metals in pharmaceutical materials; and simultaneously the amount of trimethylsilyl trifluoromethanesulfonate and reaction conditions are controlled so as to increase the body burden of beta in the product.
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Paragraph 0041; 0046; 0049; 0050
(2018/02/04)
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- Decitabine a process for the preparation of
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The invention discloses a preparation method of decitabine. The preparation method comprises the steps: oxygen methylation of 1st-site hydroxyl of 2-deoxy-D-ribose; protection for hydroxyls on a 3rd site and a 5th site; acylation of 1st-site oxygen methyle; activation of 5-azacytosine; and coupled reaction of protected 2-deoxy-D-ribose and the activated 5-azacytosine, purification of a coupling product; deprotection; and obtaining of a target product. According to the preparation method, the purity of the decitabine is improved, the purification steps of a final product are simplified, and the product cost is lowered.
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Paragraph 0068; 0070-0071; 0075; 0079; 0083
(2018/07/10)
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- FLUORINATED PYRIMIDINE ANALOGS AND METHODS OF USE THEREOF
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Fluorinated pyrimidine analog compounds, fluorinated pyrimidine analog compounds are including composition, fluorinated pyrimidine analogs method for preparing the compounds of, fluorinated pyrimidine analog compounds administering by inhibiting ladle sacrifice trans DNA, for treating solid tumors, method of treating multiple myeloma is provided. (by machine translation)
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Paragraph 0064; 0067; 0070
(2017/01/02)
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- FLUORINATED PYRIMIDINE ANALOGS AND METHODS OF USE THEREOF
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Fluorinated pyrimidine analog compounds, compositions that include the fluorinated pyrimidine analog compounds, methods for making the fluorinated pyrimidine analog compounds, and methods for inhibiting DNA methyltransferase, treating solid tumors, and treating hematologic cancers by administering the fluorinated pyrimidine analog compounds.
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Page/Page column 11; 14
(2014/09/29)
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- FLUORINATED PYRIMIDINE ANALOGS AND METHODS OF USE THEREOF
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Fluorinated pyrimidine analog compounds, compositions that include the fluorinated pyrimidine analog compounds, methods for making the fluorinated pyrimidine analog compounds, and methods for inhibiting DNA methyltransferase, treating solid tumors, and treating hematologic cancers by administering the fluorinated pyrimidine analog compounds.
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Paragraph 0074
(2014/02/16)
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- An improved and scalable process for the synthesis of 5-azacytidine: An antineoplastic drug
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An improved, practical, and scalable process for the manufacture of antineoplastic drug, 5-azacytidine (1), is described. A thorough understanding of the reaction parameters and stability of the reaction intermediates led us to the development of a robust process. The challenges in the isolation and systematic approach used to streamline the process into a very robust and practical manufacturing process are described.
- Vujjini, Satish Kumar,Varanasi, Ganesh,Arevelli, Srinivas,Kandala, Sreenatha Charyulu,Tirumalaraju, Satyanarayana Raju,Bandichhor, Rakeshwar,Kagga, Mukkanti,Cherukupally, Praveen
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p. 303 - 306
(2013/04/10)
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- SYSTHESIS OF 5-AZACYTIDINE
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Provided herein are processes for the preparation of 5-azacytidine, useful for treating, preventing, and/or managing diseases or conditions including cancer, disorders related to abnormal cell proliferation, hematologic disorders, and myelodysplastic syndromes (MDS), wherein 5-azacytidine is represented by the structure:
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Page/Page column 73
(2012/10/18)
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- PREPARATION OF DECITABINE
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The present application relates to processes for the preparation and purification of decitabine, and to processes for the preparation of a crystalline form of decitabine.
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Page/Page column 26-27
(2010/11/18)
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- PROCESS FOR PREPARING AZACYTIDINE INTERMEDIATE
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The present invention provides a processes for preparing 5 -Azacytidine, and intermediates thereof, said process Comprising reacting a silylated 5-azacytosine of the formula (II), a sugar moiety having of the formula (III): and a protic acid; wherein R is a substituted or non substituted C1-C20 acyl moiety, R1, R2 and R3 are each independently H or an alkyl group, and X is a halogen. The present invention further provides an analytical method for determining the purity of 5-Azacytidine in a sample.
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Page/Page column 18
(2010/04/03)
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- Process for Making 5-Azacytosine Nucleosides and Their Derivatives
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A process of synthesizing a 5-azacytosine nucleoside, such as azacitidine and decitabine, comprises coupling a silylated 5-azacytosine with a protected D-ribofuranose of formula in the presence of a sulfonic acid catalyst.
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Page/Page column 7
(2010/03/02)
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- AZACITIDINE PROCESS AND POLYMORPHS
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Processes for preparing azacitidine. Further included are processes for the preparation of crystalline azacitidine crystalline Form (I) and mixtures of azacitidine crystalline Forms (I) and (II).
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Page/Page column 25
(2010/04/03)
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- PROCESSES FOR PRODUCING DECITABINE
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New processes for producing decitabine are provided.
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Page/Page column 5
(2010/10/19)
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- PROCESS FOR PREPARING AZACYTIDINE INTERMEDIATE
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The present invention provides a processes for preparing 5-Azacytidine, and intermediates thereof. The present invention further provides an analytical method for determining the purity of 5-Azacytidine in a sample.
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- STABLE HIGHLY PURE AZACITIDINE AND PREPARATION METHODS THEREFOR
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Disclosed herein are methods of obtaining highly pure 5-azacytidine, which contains minimal amounts of degradation impurities and methods of assessing the impurity profile of the degradation of cytidine analogues, such as 5-azacytidine
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Page/Page column 15-16
(2009/03/07)
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- Method of producing 2' -deoxy-5-azacytidine (Decitabine)
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Summary Method of producing 2'-deoxy-5-azacytidine (Decitabine) by providing a compound of formula (I): wherein R is a removable substituent known per se; and R1 is a glycoside donor preferably a 1-halogen derivative, an imidate preferably the trichloromethyl derivative, or a thio-alkyl derivative; further providing a silylated base of formula (II): wherein R2 is a protecting group, preferably a trimethylsilyl TMS)-residue; reacting the compound of formula (I) and the compound of formula (II) together in a suitable anhydrous solvent and in the presence of a suitable catalyst; and removing the substituents R from the compound obtained in order to obtain the compound 2'-deoxy-5-azacytidine (Decitabine), characterized in that said catalyst is selected from the group comprising a salt of an aliphatic sulphonic acid and/or the salt of a optionally substituted aromatic sulphonic acid.
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Page/Page column 3-4
(2009/05/29)
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- Synthesis and antiproliferative activities of 5-azacytidine analogues in human leukemia cells
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Twenty-six 5-azacytidine analogues have been synthesized, including 4-amino-6-alkyl-1-pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 1a-j, 6-amino-4-alkyl/aryl-1-pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 2a-f and 4-amino-6-alkyl-1,3,5-triazin-2-yl-1-thio-pyranosides/ribofuranosides 3a-j. The antiproliferative activities of these synthetic analogues were investigated in human leukemia HL-60 cells. Ribofuranosyl S-nucleoside 3a, a bioisostere of 5-azacytidine, had a similar antiproliferative ability as that of the latter. Introduction of a methyl at the 6 position of 5-azacytidine and/or replacement of the ribofuranosyl moiety with pyranosyl sugars or disaccharides significantly decreased the antiproliferative activities of the 5-azacytidine derivatives. Several compounds with the replacement of pyranosyl sugars enhanced all-trans retinoic acid-induced differentiation ability in human leukemia HL-60 cells.
- Guo, Gang,Li, Gang,Liu, Dan,Yang, Qian-Jiao,Liu, Yu,Jing, Yong-Kui,Zhao, Lin-Xiang
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p. 1487 - 1500
(2008/12/22)
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- Synthesis of 5-azacytidine
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The present invention provides a method for the preparation of 5-azacytidine, wherein 5-azacytidine is represented by the structure: The method involves the silylation of 5-azacytosine, followed by the coupling of silylated 5-azacytosine to a protected β-D-ribofuranose derivative. The coupling reaction is catalyzed by trimethylsilyl trifluoromethanesulfonate (TMS-Triflate).
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- Monocyclic L-nucleosides, analogs and uses thereof
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Novel monocyclic L- nucleoside compounds have general formula (I). Embodiments of these compounds are contemplated to be useful in treating a wide variety of diseases including infections, infestations, neoplasms, and autoimmune diseases. Viewed in terms of mechanism, embodiments of the novel compounds show immunomodulatory activity, and are expected to be useful in modulating the cytokine pattern, including modulation of Th 1 and Th 2 response.
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- Synthesis and biological evaluation of 1,3-oxathiolane 5-azapyrimidine, 6-azapyrimidine, and fluorosubstituted 3-deazapyrimidine nucleosides
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(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4- triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)- 1, 3-oxathiolan-5-yl]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]- 1,3-oxathiolan-5-yl}cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.
- Liu, Mao-Chin,Luo, Mei-Zhen,Mozdziesz, Diane E.,Lin, Tai-Shun,Dutschman, Ginger E.,Gullen, Elizabeth A.,Cheng, Yung-Chi,Sartorelli, Alan C.
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p. 603 - 618
(2007/10/03)
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- Synthesis of Several Pyrimidine L-Nucleoside Analogues as Potential Antiviral Agents
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β-L-5-Iodo-2'-deoxyuridine (β-L-IUdR, 7) and 1-uracil (β-L-BV-ara-U, 10) have been synthesized via a multi-step synthesis from L-arabinose. 2',3'-Dideoxy-β-L-5-azacytidine (18), 2',3'-dideoxy-β-L-2-thiocytidine (20) and their respective α-anomers, compounds 19 and 21, also were synthesized by direct coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (13) with the corresponding silylated bases, in the presence of EtAlCl2 in CH2Cl2, followed by separation of the α- and β-isomers and deblocking of the 5'-protecting groups.In addition, 2',3'-dideoxy-β-L-5-fluorocytidine (34), a potent anti-HIV and anti-HBV agent, was synthesized by an alternative methodology from 2',3'-dideoxy-β-L-5-fluorouridine (31) via a 4-triazolylpyrimidinone intermediate.These L-nucleoside analogues were tested in vitro against HIV, HBV, HSV-1, and HSV-2.Among these compounds, 2',3'-dideoxy-β-L-5-azacytidine (18) was found to show significant activity against HBV in vitro at approximately the same level as 2',3'-dideoxy-β-D-cytidine (ddC), which is a known potent anti-HBV agent.
- Lin, Tai-Shun,Luo, Mei-Zhen,Liu, Mao-Chin
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p. 1055 - 1068
(2007/10/02)
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