- Synthesis, physicochemical characteristics, and biocompatibility of self-assemble polymers bearing guanine, cytosine, uracil, and thymine moieties
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We synthesized chemically well-defined brush (i.e., comb-like) polymers bearing guanine, cytosine, uracil, or thymine moieties at the bristle ends. The polymers were stable up to 220 °C and were readily solution-processable, yielding high-quality films. Interestingly, the brush polymers favorably self-assembled to form molecular multibilayer structures stabilized by hydrogen bonding interactions among the nucleobase moieties at the bristle ends, which provided nucleobase-rich surfaces. The multibilayer-structured polymer films showed high water affinity. They also displayed selective protein adsorption, suppressed bacterial adherence, facilitated cell adhesion, and exhibited good biocompatibility in mice. The brush polymer DNA-mimicking comb-like polymers are suitable as biomaterials and in protein separation applications.
- Kim, Jin Chul,Kim, Mihee,Jung, Jungwoon,Lee, Jinseok,Ree, Brian J.,Kim, Heesoo,Kim, Ik Jung,Kim, Jung Ran,Ree, Moonhor
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- Synthesis of N4-β-D-glycoside cytosines and sugar N 4-acetylcytosin-1-ylmethylhydrazones as antiviral agents
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Reaction of monosaccharide aldoses with cytosine (1) gave stereoselectively β-N-glycosides 2a-d, which were treated with acetic anhydride in pyridine to afford the corresponding acetylated derivatives 3a-d. N4- Acetylcytosine (4) was synthesised and treated with ethyl chloroacetatete give 1-(ethoxycarbonylmethy)-N4-acetylcytosine (5). Hydrolysis of the latter ester with hydrazine hydrate afforded the hydrazide derivative 6. Condensation of the hydrazide with monosaccharide aldoses gave the corresponding sugar hydrazones 7a-f. Acetylation of the hydrazones afforded the per-O-acetyl derivatives 8a-f. The prepared compounds were tested for antiviral activity against hepatitis B virus (HBV) which showed moderate activities.
- Ali, Omar M.,Amer, Hamada H.,Abdel-Rahman, Adel A.-H.
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- Discovery of α-aminoazaheterocycle-methylglyoxal adducts as a new class of high-affinity inhibitors of cystic fibrosis transmembrane conductance regulator chloride channels
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The cystic fibrosis transmembrane conductance regulator (CFTR) represents the main Cl- channel in the apical membrane of epithelial cells for cAMP-dependent Cl- secretion. Here we report on the synthesis and screening of a small library of nontoxic α-aminoazaheterocycle- methylglyoxal adducts, inhibitors of wild-type (WT) CFTR and G551D-, G1349D-, and F508del-CFTR Cl- channels. In whole-cell patch-clamp experiments of Chinese hamster ovary (CHO) cells expressing WT-CFTR, we recorded rapid and reversible inhibition of forskolin-activated CFTR currents in the presence of the adducts 5a and 8a,b at 10 pM concentrations. Using iodide efflux experiments, we compared concentration-dependent inhibition of CFTR with glibenclamide (IC50 = 14.7 μM), 3-[(3-trifluoromethyl)phenyl]-5- [(4-carboxyphenyl-)methylene]-2-thioxo-4-thiazolidinone (CFTRinh-172) (IC50 = 1.2 μM), and α-aminoazaheterocycle-methylglyoxal adducts and identified compounds 5a (IC50 = 71 pM), 8a,b (IC 50 = 2.5 nM), and 7a,b (IC50 = 3.4 nM) as the most potent inhibitors of WT-CFTR channels. Similar ranges of inhibition were also found when these compounds were evaluated on CFTR channels with the cystic fibrosis mutations F508del (in temperature-corrected human airway epithelial F508del/F508del CF15 cells)-, G551D-, and G1349D-CFTR (expressed in CHO and COS-7 cells). No effect of compound 5a was detected on the volume-regulated or calcium-regulated iodide efflux. Picomolar inhibition of WT-CFTR with adduct 5a was also found using a 6-methoxy-N-(3-sulfopropyl)-quinolinium fluorescent probe applied to the human tracheobronchial epithelial cell line 16HBE14o-. Finally, we found comparable inhibition by 5a or by CFTRinh-172 of forskolin-dependent short-circuit currents in mouse colon. To the best of our knowledge, these new nontoxic α-aminoazaheterocycle-methylglyoxal adducts represent the most potent compounds reported to inhibit CFTR chloride channels. Copyright
- Routaboul, Christel,Norez, Caroline,Melin, Patricia,Molina, Marie-Carmen,Boucherle, Benjamin,Bossard, Florian,Noel, Sabrina,Robert, Renaud,Gauthier, Chantal,Becq, Frederic,Decout, Jean-Luc
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- N -Glycosylation with sulfoxide donors for the synthesis of peptidonucleosides
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The synthesis of glycopyranosyl nucleosides modified in the sugar moiety has been less frequently explored, notably because of the lack of a reliable method to glycosylate pyrimidine bases. Herein we report a solution in the context of the synthesis of peptidonucleosides. They were obtained after glycosylation of different pyrimidine nucleobases with glucopyranosyl donors carrying an azide group at the C4 position. A methodological study involving different anomeric leaving groups (acetate, phenylsulfoxide and ortho-hexynylbenzoate) showed that a sulfoxide donor in combination with trimethylsilyl triflate as the promoter led to the best yields.
- Beau, Jean-Marie,Beretta, Margaux,Dr?ge, Thomas,Es-Sayed, Mazen,Nicolas, Lionel,Norsikian, Stéphanie,Rouchaud, Emilie,Vors, Jean-Pierre
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supporting information
p. 4285 - 4291
(2021/05/31)
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- Preparation method for synthesizing palbociclib intermediate and method for synthesizing palbociclib
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The invention discloses a preparation method of a novel palbociclib intermediate. The method is characterized by comprising the following steps: taking cytosine as a raw material, through protection of the amino group of cytosine, using an acetylation agent to perform acylation to obtain a 5- acetylation product in the presence of a Lewis acid or other acidic reagents, performing de-protection toobtain 5-acetylcytosine, and performing bromo-cyclopentane substitution and methyl acetoacetate cyclization to obtain a key pyridopyrimidine intermediate, which can be used for preparing palbociclib.The method has the advantages of short reaction route, cheap and easily available cytosine serving as an initial raw material, mild reaction conditions, high total yield, suitability for industrial production, and the like.
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Paragraph 0018
(2020/09/30)
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- Stereoselective N-glycosylation with N4-acyl cytosines and efficient synthesis of gemcitabine
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Through systematical comparison of various N4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta-stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N4-Bz cytosine and anomeric mixture of 2,2‘-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine.
- Liu, Tongchao,Tang, Jiadeng,Liang, Jianpeng,Chen, Yabin,Wang, Xiaowen,Shen, Jingkang,Zhao, Dongmei,Xiong, Bing,Cen, Jun-Da,Chen, Yue-Lei
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p. 1203 - 1213
(2019/01/29)
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- Synthesis and in vitro activity of N-sulfonylamidine-derived Pyrimidine Analogues
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Two novel series of N-sulfonylamidino pyrimidine derivatives were synthesized via Cu-catalyzed three-component reaction of propargylated nucleobases with different benzenesulfonyl azides and amines. In this way 4-acetamido, 4 -methyl and 4-carboxybenzenesulfonyl amidine products 15-26 in the uracil series and 4-acetamidobenzenesulfonyl amidine derivatives 27-29 in the cytosine series were prepared in 34-69 % yields. Attempts to prepare N-sulfonylamidino cytosine derivatives in reaction with 4-methylbenzenesulfonyl azide were unsuccessful. The cytosine derivatives 32 and 33 were prepared from the N-sulfonylamidino uracil derivatives via the C4 triazole intermediates. The prepared N-sulfonylamidino pyrimidine derivatives 1-28 were tested for the antiproliferative activity on a panel of seven tumor cell lines of different histological origin (HeLa, Caco-2, NCI-H358, Raji, HuT78, K562, Jurkat) and on normal MDCK I cells. Most of the synthesized compounds showed antiproliferative activity on the tested cell lines.
- Krstulovi?, Luka,Safti?, Dijana,Ismaili, Hamit,Baji?, Miroslav,Glava?-Obrovac, Ljubica,?ini?, Biserka
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p. 625 - 636
(2018/05/07)
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- PROCESS FOR PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE
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The present invention relates to a novel and stereoselective synthetic process for the preparation of optically active cis-nucleoside derivatives of compound of Formula (I), wherein R3 represents H, F, Cl, C1-16 alkyl.
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Page/Page column 8
(2011/11/30)
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- PROCESS FOR THE PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE
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The present invention relates to a novel and stereoselective synthetic process for the preparation of optically active cis-nucleoside derivatives of compound of Formula (I), wherein R3 represents H, F, Cl, C1-16 alkyl.
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Page/Page column 18
(2010/08/08)
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- Method for the treatment or prevention of viral infection using nucleoside analogues
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Compounds of formula I: wherein Y, X, R1 and Ra are defined herein are in methods for treating or preventing a viral infections selected from herpes simplex virus, varicella zoster virus, respiratory syncytial virus and cytomegalovirus infections.
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- Methods of treating cancer using a combination of drugs
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The present invention provides a novel method for treating a patient with cancer comprising administering to the patient a therapeutically effective amount of cisplatin and a compound having the formula I: wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, and wherein each Rc is independently selected from the group comprising H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and a hydroxy protecting group.
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- Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives
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A series of pyrimidinone derivatives of thiazolidinediones were synthesized. Their biological activity were evaluated in insulin resistant, hyperglycemic and obese db/db mice. In vitro PPARγ transactivation assay was performed in HEK 293T cells. PMT13 showed the best biological activity in this series. PMT13 (5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy] phenylmethyl]thiazolidine-2,4-dione) showed better plasma glucose, triglyceride and insulin-lowering activity in db/db mice than rosiglitazone and pioglitazone. PMT13 showed better PPARγ transactivation than the standard compounds. Pharmacokinetic study in Wistar rats showed good systemic exposure of PMT13. Twenty-eight day oral toxicity study in Wistar rats did not show any treatment-related adverse effects.
- Madhavan, Gurram R,Chakrabarti, Ranjan,Vikramadithyan, Reeba K,Mamidi, Rao N.V.S,Balraju,Rajesh,Misra, Parimal,Kumar, Sunil K.B,Lohray, Braj B,Lohray, Vidya B,Rajagopalan, Ramanujam
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p. 2671 - 2680
(2007/10/03)
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- Methods of treating leukemia
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The present invention provides a novel method for treating leukemia and more particularly acute myelogenous leukemia (AML) in a host comprising administering to the host a therapeutically effective amount of a compound having the formula I: wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, and wherein each Rc is independenty selected from the group comprising H, C1-6 alkyl, C2-6 alkynyl and an hydroxy protecting group; and wherein said compound is substantially in the form of the (?) enantiomer.
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- Method and compositions for the synthesis of dioxolane nucleosides with β configuration
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The present invention relates to methods and compositions for preparing biologically important nucleoside analogues containing 1,3-dioxolane sugar rings. In particular, this invention relates to the stereoselective synthesis of the beta (cis) isomer by glycosylating the base with an intermediate of formula (II) below a temperature of about -10° C. STR1 wherein R1 and L are defined herein.
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- Chlorothioketene, the ultimate reactive intermediate formed by cysteine,conjugate β-lyase-mediated cleavage of the trichloroethene metabolite S-(1,2-dichlorovinyl)-L-cysteine, forms cytosine adducts in organic solvents, but not in aqueous solution
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Chlorothioketene has been suggested as a reactive intermediate formed by the cysteine conjugate β-lyase-mediated cleavage of S-(1,2-dichlorovinyl)- L-cysteine, a minor metabolite of trichloroethene. Halothioketenes are highly reactive, and their intermediate formation may be confirmed by reactions such as cycloadditions and thioacylations of nucleophiles. A precursor of chlorothioketene, S-(1,2-dichlorovinyl)thioacetate, is readily accessible by the reaction of dichloroethyne with thioacetic acid. In presence of base, S- (1,2-dichlorovinyl)thioacetate is cleaved to chlorothioketene. Chlorothioketene is not stable at room temperature and was characterized after transformation to stable products by reaction with compounds such as cyclopentadiene, N,N-diethylamine, and ethanol. In organic solvents, the cleavage of S-(1,2-dichlorovinyl)thioacetate in the presence of cytosine results in N4-acetylcytosine, N4-(chlorothioacetyl)cytosine; and small amounts of 3-(N4-thioacetyl)cytosine. No reaction products were seen with guanosine, adenosine, and thymidine under identical conditions. When cytosine was reacted with S-(1,2-dichlorovinyl)thioacetate in aqueous solutions, only N4-acetylcytosine was formed. N4-(Chlorothioacetyl)cytosine and 3-(N4- thioacetyl)cytosine were not detected even when using a very sensitive method, derivatization with pentafluorobenzyl bromide and electron capture mass spectrometry with a detection limit of 50 fmol/μL of injection volume. Aqueous solutions of DNA cleave S-(1,2-dichlorovinyl)thioacetate to give N4- acetyldeoxycytidine in DNA, but chlorothioketene adducts of deoxynucleosides were also not detected in these experiments. These results confirm the electrophilic reactivity of chlorothioketene toward nucleophilic groups of DNA constituents in inert solvents but also demonstrate that the formation of DNA adducts under physiological conditions likely is not efficient. Therefore, DNA adducts may not represent useful biomarkers of exposure and biochemical effects for trichloroethene.
- Voelkel, Wolfgang,Dekant, Wolfgang
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p. 1082 - 1088
(2007/10/03)
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- AMIDOALKYLATION OF PYRIMIDINE BASES OF NUCLEIC ACIDS
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The reaction of uracil, thymine, and cytosine with acid N-α-chloroalkylamides gave N-substituted derivatives of these compounds.Conditions for the selective amidoalkylation of pyrimidine bases in the 1 position were found.
- Khutova, B. M.,Klyuchko, S. V.,Prikazchikova, L. P.
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p. 407 - 409
(2007/10/02)
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- 13C-enriched ribonucleosides: Synthesis and application of 13C-1H and 13C-13C spin-coupling constants to assess furanose and N-glycoside bond conformations
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Adenosine (1), cytidine (2), guanosine (3), and uridine (4) have been prepared chemically with 13C enrichment (99 atom %) at C1′ and C2′ of the ribose ring. Reliable synthetic protocols have been developed to permit access to millimole quantities of labeled ribonucleosides required for structural studies of stable isotopically labeled oligonucleotides and for in vivo metabolism studies. High-resolution 1H and 13C NMR spectra of the enriched ribonucleosides have been obtained, and 13C-13C and 13C-1H spin-coupling constants have been measured for pathways within the β-D-ribofuranose ring and across the N-glycoside bond. Related couplings were determined in methyl α- and β-D-ribofuranosides (5, 6), and in two conformationally constrained nucleosides, 2,2′-anhydro-(1-β-D-arabinofuranosyl)uracil (7) and 2′,3′-O-isopropylidene-2,5′-O-cyclouridine (8). The latter data were used to construct a crude Karplus curve for the 13C-C-N-13C coupling pathway across the N-glycoside bond in 1-4. 1H-1H, 13C-1H, and 13C-13C coupling data are used to evaluate current models describing the conformational dynamics of 1-4 in aqueous solution.
- Kline, Paul C.,Serianni, Anthony S.
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p. 7373 - 7381
(2007/10/02)
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- 2' AND 3'-KETONUCLEOSIDES AND THEIR ARABINO AND XYLO REDUCTION PRODUCTS CONVENIENT ACCESS VIA SELECTIVE PROTECTION AND OXIDATION OF RIBONUCLEOSIDES
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A number of 2',5'- or 3',5'-diprotected ribonucleosides and 5'-protected 2'- or 3'-deoxy-β-D-erythro-pentofuranosyl nucleosides have been oxidized to the corresponding 3' or 2'-ketonucleoside derivatives using chromium trioxide/pyridine/acetic anhydride or dimethyl sulfoxide/acetic anhydride.Reduction of the carbonyl functions with sodium borohydride gave the inverted arabino, xylo, or deoxy-threo isomers as predominant products by attack at the less hindered α-face of the sugar ring.Parallel reductions using sodium borodeuteride corroborated the epimeric ratios by demonstrating that complete oxidation of the original hydroxyl groups had occured.The deuterium labeling also aided in making NMR spectral assignments.
- Hansske, Fritz,Madej, Danuta,Robins, Morris J.
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p. 125 - 135
(2007/10/02)
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- PREPARATION OF THE 1-(2,5-ANHYDRO-β-D-ARABINOFURANOSYL) DERIVATIVE OF CYTOSINE AND URACIL AND THEIR CLEAVAGE WITH HYDROGEN BROMIDE
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Anhydronucleoside Ia was prepared from chloroarabinofuranoxylcytosine IIIc or from 2,2'-anhydro-1-(5-chloro-5-deoxy-β-D-arabinofuranosyl)cytosine by the action of a strongly basic ion exchanger.The anhydro derivative IIa was prepared from 2,2'-anhydro-1-(5-chloro-5-deoxy-β-D-arabinofuranosyl)uracil by treatment with aqueous solution of sodium hydroxide.The action of hydrogen bromide in dimethylformamide on 2',5'-anhydronucleosides Ia and IIa leads both to the cleavage of the anhydro bond under formation of the 5'-bromo derivatives IIIa and IVa and to the cleavage of nucleosidic bond.In case of uracil derivative IIa, the α-arabinofuranosyl derivative V was also isolated after preceding acetylation.For unambiguous proof of the structure, an alternative synthesis of compound V was performed.
- Hrebabecky, Hubert,Brokes, Josef,Beranek, Jiri
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p. 2961 - 2968
(2007/10/02)
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