cas 5987-73-5, 2,3,5-TRI-O-ACETYL-6-CHLOROPURINE-9-?-D-RIBOFURANOSIDE

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Modification of Nucleic Acid Bases via Radical Intermediates: Synthesis of Dihalogenated Purine Nucleosides
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Nair, Vasu,Richardson, Stephen G.
p. 670 - 672
(1982)
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C6 substitution of inosine using hexamethylphosphorous triamide in conjunction with carbon tetrahalide or N-halosuccinimide
Herein we report the facile conversion of 2',3',5'-tri-O- acetylinosine to three different nucleoside analogs via reaction of hexamethylphosphorous triamide and an organic halide. Acetyl-protected 6-bromopurine riboside, 6- chloropurine riboside and N6,N6-dimethyladenosine can each be prepared in good yield from 2',3',5'-tri-O-acetylinosine, HMPT and halide. The major product of the reaction is determined by the identity of the halide used and the reaction temperature. (C) 2000 Elsevier Science Ltd.
Véliz, Eduardo A.,Beal, Peter A.
p. 1695 - 1697
(2000)
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Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA
TEMPO spin labels protected with 2-nitrobenzyloxymethyl groups were attached to the amino residues of three different nucleo-sides: deoxycytidine, deoxyadenosine, and adenosine. The corresponding phosphoramidites could be incorporated by unmodified standa
Weinrich, Timo,Jaumann, Eva A.,Scheffer, Ute M.,Prisner, Thomas F.,G?bel, Michael W.
p. 1563 - 1569
(2018)
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Crystal form, preparation method and purpose of triacetyl-3-hydroxyphenyl adenosine
The invention relates to a crystal form, a preparation method and a purpose of hyperlipemia-treating medicine of triacetyl-3-hydroxyphenyl adenosine. The crystal form of the triacetyl-3-hydroxyphenyl adenosine comprises a type I crystal and a type II crystal of 2',3',5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine with a blood-lipid regulating effect, wherein the type I crystal has an X-ray powder diffraction pattern as shown in Figure 1, and the type II crystal has an X-ray powder diffraction pattern as shown in Figure 4.
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(2021/06/22)

Highly efficient chemical phosphorylation of 6-(4-phenylpiperazine-1-yl)-9-(β-D-ribofuranosyl)-9H-purine
Antimetabolites, which are metabolic antagonists used in the treatment of cancer and viral diseases by replacing metabolites, inhibit the action of metabolic enzymes and disrupt the pathways of synthesis of structural units necessary for the formation of
Polat, M. Fatih,Tuncbilek, Meral
p. 233 - 241
(2021/01/18)

The isoprenoid derivative N6-benzyladenosine CM223 exerts antitumor effects in glioma patient-derived primary cells through the mevalonate pathway
Background and Purpose: N6-Isopentenyladenosine (i6A) is a modified nucleoside exerting in vitro and in vivo antiproliferative effects. We previously demonstrated that the actions of i6A correlate with the expression and activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway, which is aberrant in brain cancer. To develop new anti-glioma strategies, we tested related compounds exhibiting greater activity than i6A. Experimental Approach: We designed and synthesized i6A derivatives characterized by the introduction of diverse chemical moieties in the N6 position of adenosine and tested for their efficacy in U87 cells and in primary glioma cultures, derived from patients. NMR-based structural analysis, molecular docking calculations and siRNA mediated knockdown were used to clarify the molecular basis of their action, targeting FPPS protein. Key Results: CM223, the i6A derivative including a benzyl moiety in N6 position of adenine, showed marked activity in selectively targeting glioma cells, but not normal human astrocytes. This was due to induction of intrinsic pathways of apoptosis and inhibition of proliferation, along with blockade of FPPS-dependent protein prenylation, which counteracted oncogenic signalling mediated by EGF receptors. Conclusion and Implications: The biological effects together with structural data on interaction of CM223 with FPPS, provided additional evidence for the correlation of the i6A/CM223 antitumor activity with FPPS modulation. Because the MVA pathway is an important promising target, CM223 and its derivatives should be considered interesting active molecules in antiglioma research.
Ciaglia, Elena,Grimaldi, Manuela,Abate, Mario,Scrima, Mario,Rodriquez, Manuela,Laezza, Chiara,Ranieri, Roberta,Pisanti, Simona,Ciuffreda, Pierangela,Manera, Clementina,Gazzerro, Patrizia,D'Ursi, Anna Maria,Bifulco, Maurizio
supporting information
p. 2287 - 2301
(2017/06/28)

Indole- and Pyrrole-BX: Bench-Stable Hypervalent Iodine Reagents for Heterocycle Umpolung
The one-step synthesis of the bench-stable hypervalent iodine reagents IndoleBX and PyrroleBX using mild Lewis acid catalyzed conditions is reported. The new reagents are stable up to 150 °C and were applied in the C?H arylation of unactivated arenes using either rhodium or ruthenium catalysts. A broad range of heterocyclic systems of high interest for synthetic and medicinal chemistry was accessed in high yields. The developed C?H functionalization could not be achieved using reported reagents or methods, highlighting the unique reactivity of Indole- and Pyrrole-BX.
Caramenti, Paola,Nicolai, Stefano,Waser, Jerome
supporting information
p. 14702 - 14706
(2017/09/11)

PROBE FOR IMAGING PARP-1 ACTIVITY
Provided are embodiments of a small molecule tracer for positron emission tomography (PET) imaging of the enzyme activity of PARP-1 that is responsible for DNA-damage sensing and critically involved in radiation therapy and some chemotherapy response mechanisms. These PARP-1 tracers are derivatives of nicotinamide adenine dinucleotide (NAD), which is the natural substrate for PARP-1. Provided are NAD derivatives that include a linker moiety to which may be attached a label moiety such as a PET detectable fluorine to generate a 6N-(triazo-PEG2-18F)-NAD. Especially advantageous for use in PET and MRI scanning detection systems is the attachment of a chelating agent that allows for the formation of a chelator-metal ion complex.
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Paragraph 0144; 0145

(2016/08/03)

Synthesis of nelarabine with pure β-anomer through late-stage C-H nitration/nitro-reduction
An efficient and pure β-anomer synthesis of the clinical drug nelarabine from the readily available vidarabine has been achieved for the first time. The C6 amino group of vidarabine was transformed to methoxy group by diazotization/chlorination followed by methoxylation using Na2CO3/MeOH system. The formation of C(2)-N bond was achieved via the highly selective C-H bond functionalization by reacting with 2,2,2-trifluoroacetic anhydride (TFAA) and tetrabutylammonium nitrate. The final product was obtained in total yield of 58.6% by 5 steps-synthesis from vidarabine after the reduction of nitro group to amino group. Moreover, the drug nelarabine could be obtained in 100 grams scale successfully and no chromatography was needed, which made this route more attractive for industrial application.
Xia, Ran,Sun, Li-Ping,Qu, Gui-Rong
p. 2386 - 2393
(2016/03/01)

2-catalyzed directed N -Boc amidation of arenes "on water"
Rhodium(III) catalysis "on water" is effective for directed C-H amidation of arenes. The catalytic process is promoted by OH groups present on the hydrophobic water surface and is inefficient in all (most) common organic solvents investigated so far. In the presence of easily prepared tert-butyl 2,4-dinitrophenoxycarbamate, a new and stable nitrene source, the "on water" reaction can efficiently provide the desired N-Boc-aminated products with good functional group tolerance.
Ali, Md Ashif,Yao, Xiayin,Sun, Hao,Lu, Hongjian
supporting information
p. 1513 - 1516
(2015/03/30)

α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors
ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.
Bhattarai, Sanjay,Freundlieb, Marianne,Pippel, Jan,Meyer, Anne,Abdelrahman, Aliaa,Fiene, Amelie,Lee, Sang-Yong,Zimmermann, Herbert,Yegutkin, Gennady G.,Str?ter, Norbert,El-Tayeb, Ali,Müller, Christa E.
p. 6248 - 6263
(2015/08/24)

Synthesis and evaluation of the substrate activity of C-6 substituted purine ribosides with E. coli purine nucleoside phosphorylase: Palladium mediated cross-coupling of organozinc halides with 6-chloropurine nucleosides [1]
A series of C-6 alkyl, cycloalkyl, and aryl-9-(β-d-ribofuranosyl) purines were synthesized and their substrate activities with Escherichia coli purine nucleoside phosphorylase (E. coli PNP) were evaluated. (Ph 3P)4Pd-mediated cross-c
Hassan, Abdalla E.A.,Abou-Elkhair, Reham A.I.,Riordan, James M.,Allan, Paula W.,Parker, William B.,Khare, Rashmi,Waud, William R.,Montgomery, John A.,Secrist III, John A.
experimental part
p. 167 - 174
(2012/03/08)

Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L
Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with Ki values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC50 values of 4-11 μM. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-l-methionine) but not the substrate nucleosome.
Anglin, Justin L.,Deng, Lisheng,Yao, Yuan,Cai, Guobin,Liu, Zhen,Jiang, Hong,Cheng, Gang,Chen, Pinhong,Song, Yongcheng,Dong, Shuo
supporting information
p. 8066 - 8074,9
(2020/09/15)

Aberrant cyclization affords a C-6 modified cyclic adenosine 5′-diphosphoribose analogue with biological activity in Jurkat T cells
Two nicotinamide adenine dinucleotide (NAD+) analogues modified at the 6 position of the purine ring were synthesized, and their substrate properties toward Aplysia californica ADP-ribosyl cyclase were investigated. 6-N-Methyl NAD+ (6-N-methyl nicotinamide adenosine 5′-dinucleotide 10) hydrolyzes to give the linear 6-N-methyl ADPR (adenosine 5′-diphosphoribose, 11), whereas 6-thio NHD+ (nicotinamide 6-mercaptopurine 5′-dinucleotide, 17) generates a cyclic dinucleotide. Surprisingly, NMR correlation spectra confirm this compound to be the N1 cyclic product 6-thio N1-cIDPR (6-thio cyclic inosine 5′-diphosphoribose, 3), although the corresponding 6-oxo analogue is well-known to cyclize at N7. In Jurkat T cells, unlike the parent cyclic inosine 5′-diphosphoribose N1-cIDPR 2, 6-thio N1-cIDPR antagonizes both cADPR- and N1-cIDPR-induced Ca2+ release but possesses weak agonist activity at higher concentration. 3 is thus identified as the first C-6 modified cADPR (cyclic adenosine 5′-diphosphoribose) analogue antagonist; it represents the first example of a fluorescent N1-cyclized cADPR analogue and is a new pharmacological tool for intervention in the cADPR pathway of cellular signaling.
Moreau, Christelle,Kirchberger, Tanja,Zhang, Bo,Thomas, Mark P.,Weber, Karin,Guse, Andreas H.,Potter, Barry V. L.
supporting information; experimental part
p. 1478 - 1489
(2012/04/23)

TRIACETYL-3-HYDROXYPHENYLADENOSINE AND ITS USE FOR REGULATING BLOOD FAT
The invention discloses triacetyl-3-hydroxyphenyladenosine represented by formula (I), the preparation, the pharmaceutical composition and the use thereof. Specially, the invention discloses a new compound of 2',3',5'-tri-O-acetyl-N6-(3-hydroxyphenyl)adenosine. Using hypoxanthine nucleoside as starting material, the compound is prepared by acetylating with acetic anhydride, chlorinating with thionyl chloride, and being substituted with 3-hydroxy aniline. The invention also discloses the pharmaceutical composition comprising triacetyl-3-hydroxyphenyladenosine. The dosage forms of the said pharmaceutical composition include tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or particulate delivery system. The medicament for treatment or precaution of hyperlipemia prepared by the compound of the invention has the advantages of significant hypolipidemic activity, less toxicity and adverse effect as well as slow metabolism in vivo.
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(2012/02/04)

Synthesis of novel 6-(4-substituted piperazine-1-yl)-9-(β-d- ribofuranosyl)purine derivatives, which lead to senescence-induced cell death in liver cancer cells
Novel purine ribonucleoside analogues (9-13) containing a 4-substituted piperazine in the substituent at N6 were synthesized and evaluated for their cytotoxicity on Huh7, HepG2, FOCUS, Mahlavu liver, MCF7 breast, and HCT116 colon carcinoma cell lines. The purine nucleoside analogues were analyzed initially by an anticancer drug-screening method based on a sulforhodamine B assay. Two nucleoside derivatives with promising cytotoxic activities (11 and 12) were further analyzed on the hepatoma cells. The N6-(4- Trifluoromethylphenyl)piperazine analogue 11 displayed the best antitumor activity, with IC50 values between 5.2 and 9.2 μM. Similar to previously described nucleoside analogues, compound 11 also interferes with cellular ATP reserves, possibly through influencing cellular kinase activities. Furthermore, the novel nucleoside analogue 11 was shown to induce senescence-associated cell death, as demonstrated by the SAβ-gal assay. The senescence-dependent cytotoxic effect of 11 was also confirmed through phosphorylation of the Rb protein by p15INK4b overexpression in the presence of this compound.
Tuncbilek, Meral,Bilget Guven, Ebru,Onder, Tugce,Cetin Atalay, Rengul
experimental part
p. 3058 - 3065
(2012/06/01)

Molecular recognition at the active site of catechol-O-methyltransferase (COMT): Adenine replacements in bisubstrate inhibitors
L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrueggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC50 values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg2+ confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group. Copyright
Ellermann, Manuel,Paulini, Ralph,Jakob-Roetne, Roland,Lerner, Christian,Borroni, Edilio,Roth, Doris,Ehler, Andreas,Schweizer, W. Bernd,Schlatter, Daniel,Rudolph, Markus G.,Diederich, Francois
supporting information; scheme or table
p. 6369 - 6381
(2011/08/06)

Facile synthesis of N-6 adenosine modified analogue toward S-adenosyl methionine derived probe for protein arginine methyltransferases
Chemically modified cellular co-factors that provide function, such as immobilization or incorporation of fluorescent dyes, are valuable probes of biological activity. A convenient route to obtain S-adenosyl methionine (AdoMet) analogues modified at N-6 adenosine to feature a linker terminating in azide functionality is described herein. Subsequent decoration of such AdoMet analogues with guanidinium terminated linkers leads to novel potential bisubstrate inhibitors for protein arginine methyltransferases, PRMTs.
Hong, Wei,Dowden, James
scheme or table
p. 1439 - 1442
(2012/06/15)

Simple method for fast deprotection of nucleosides by triethylamine- catalyzed methanolysis of acetates in aqueous medium
A straightforward methodology for deacetylation of protected ribonucleosides was developed based on triethylamine-catalyzed solvolysis in aqueous methanol. Reactions are completed in a few minutes under microwave irradiation and the free nucleosides are obtained in high yield after simple evaporation of volatiles. Other important features include the involvement of readily available reagents and the compatibility with diverse functional groups, which make this process very attractive for broad application.
Meier, Lidiane,Monteiro, Gustavo C.,Baldissera, Rodrigo A.M.,Sa?, Marcus Mandolesi
body text
p. 859 - 866
(2010/09/11)

Design, synthesis and biological evaluation of a bivalent μ opiate and adenosine A1 receptor antagonist
The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A1 adenosine and μ opiate receptors with a Ki of 0.8 ± 0.05 and 0.7 ± 0.03 μM, respectively. This hybrid molecule increases cAMP production in cells that over express the μ receptor as well as those over expressing the A1 adenosine receptor and reverses the antalgic effects of μ and A1 adenosine receptor agonists in animals.
Mathew, Smitha C.,Ghosh, Nandita,By, Youlet,Berthault, Aurelie,Virolleaud, Marie-Alice,Carrega, Louis,Chouraqui, Gaelle,Commeiras, Laurent,Condo, Jocelyne,Attolini, Mireille,Gaudel-Siri, Anouk,Ruf, Jean,Parrain, Jean-Luc,Rodriguez, Jean,Guieu, Regis
scheme or table
p. 6736 - 6739
(2010/06/14)

COMPOUND HAVING INHIBITORY ACTIVITY ON A RHO-GTPASE CELL PROTEIN, A PROCESS FOR OBTAINING THE SAME, PHARMACEUTICAL COMPOSITIONS COMPRISION THEREOF AND A METHOD FOR THE TREATMENT OF A RHO-GTPASE CELL PROTEIN-MEDIATED CONDITION
The present invention relates to a compound having inhibitory activity on a Rho-GTPase cell protein, the compound having the formula I (Formula I ) wherein A is selected from N and N-H, R1 is selected from H and NHR3, R2 is selected from NHR4, OR4, O and halogen, R3 is selected from H and -COR5, R4 is selected from H, a C1-C6 alkyl and a substituted or unsubstituted phenyl, R5 is selected from a C1-C12 alkyl and a substituted or unsubstituted phenyl, R6 is selected from H, -COR5, -CO2R5, -PR7R8 and -PR7R8OPR7R8R8R7, R7 is selected from O and S, R8 is selected from H, OR4 and OSATE (-OCH2CH2SCOR5), and wherein each represents a single bond or a double bond, provided that when one of them is a double bond the other one is a single bond, and pharmaceutically acceptable salts and derivatives thereof. In particular, the compounds of the invention may be used as antitumor agents the action of which interfere with the signaling pathways normally involved in tumor development processes. The invention also relates to processes for obtaining of compounds having inhibitory activity of a Rho- GTPase cell protein, to the pharmaceutical compositions thereof and to the therapeutic methods comprising the use of said compounds and compositions.
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Page/Page column 25-26

(2008/12/05)

New fluorescent adenosine A1-receptor agonists that allow quantification of ligand-receptor interactions in microdomains of single living cells
Fluorescence spectroscopy is becoming a valuable addition to the array of techniques available for scrutinizing ligand-receptor interactions in biological systems. In particular, scanning confocal microscopy and fluorescence correlation spectroscopy (FCS) allow the noninvasive imaging and quantification of these interactions in single living cells. To address the emerging need for fluorescently labeled ligands to support these technologies, we have developed a series of red-emitting agonists for the human adenosine A1-receptor that, collectively, are N6-aminoalkyl derivatives of adenosine or adenosine 5′-N-ethyl carboxamide. The agonists, which incorporate the commercially available fluorophore BODIPY [630/650], retain potent and efficacious agonist activity, as demonstrated by their ability to inhibit cAMP accumulation in chinese hamster ovary cells expressing the human adenosine A1-receptor. Visualization and confirmation of ligand-receptor interactions at the cell membrane were accomplished using confocal microscopy, and their suitability for use in FCS was demonstrated by quantification of agonist binding in small areas of cell membrane.
Middleton, Richard J.,Briddon, Stephen J.,Cordeaux, Yolande,Yates, Andrew S.,Dale, Clare L.,George, Michael W.,Baker, Julian G.,Hill, Stephen J.,Kellam, Barrie
p. 782 - 793
(2008/01/27)

THERAPEUTIC COMPOUNDS
Use of compounds of general formula (A) as medicaments is described, in particular for the treatment of pain or inflammation; wherein: (I) when X = OH, R2 = NH2, R5 = CH2OH, R6 = H , R1 is C5-C6 alkoxy, OCH2Cyclopropyl, O-(2,2,3,3-tetrafluoro-cycloButyl), phenoxy, substituted phenoxy, OCH2CH2OH, or OCH2CHF2, (5-indanyl)oxy, C1, C2, C5, or C6 alkylamino, (R) or (S)-sec-Butylamino, C5 or C6 cycloalkylamino, exo-norbornane amino, (N-methyl, N--isoamylamino), phenylamino, phenylamino with either rnethoxy or fluoro substituents, a C2 sulfone group, a C2 alkyl group, a cyano group, a CONH2 group, or 3,5-dimethylphenyl; or when X = H, R2 = NH2, R5 = CH2OH , R6 = H, R1 is n-hexyloxy; or (II) when X = OH , R1 = H, R5 = CH2OH, R6 = H, R2 is NMe2, N-(2-isopentenyl), piperazinyl, (N-Me, N-benzyl), (N-Me, N-CH2Ph(3-Br)), (N-Me, N--CH2Ph(3-CF3)), or (N-Me, N-(2-rnethoxyethyl)), or OCH2Cyclopentyl; or (III) when X = OH, R5 = CONHR3, R6 = H: R1 is H, R3 is an isopropyl group, and R2 is either NH2 or a methylamino group (NHMe) or an isoamyl group (CH2CH2CHMe2); or R1 is H, R3 is H, and R2 is NH2; or R1 is OMe, R3 is Ph, and R2 is NH2; or R1 is NHCH2CH2CH2CH2CH2Me, R3 is CH2CH2CH2Me, and R2 is NH2; or (IV) when X = OH, R1 = H, R2 = NH2, R5 = CH2NHCOR.4, R6 = H, R4 is n-propyl or NHCH2CH3; or (V) when X = OH, R5 = CH2OH, R6 = H: R1 is NHCyclohexyl when R2 is NMe2; or R1 is OMe when R2 is NHBenzyl; or (VI) when X = OH , R2 = NH2, R5 = CH2OH, R6 = Me, R1 is NHCyclohexyl or NHCyclopentyl.
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Page/Page column 42

(2008/06/13)

PROCESSES FOR PRODUCTION OF NUCLEOSIDES
The present invention relates to a production method of a nucleoside compound represented by the formula [II] which includes subjecting a 2',3',5'-triacyloxynucleoside compound represented by the formula [I] to deacylation using alkali metal hydroxide in a 0.01- to 0.5-fold amount in a molar ratio relative to the 2',3',5'-triacyloxynucleoside compound. According to the present invention, a production method of a nucleoside compound of the formula [II] which suppresses a by-product, and a production method of a nucleoside derivative which utilizes this method can be provided. In addition, the present invention relates to oxidation of a nucleoside compound represented by the formula (1) in the presence of a 2,2,6,6-tetramethylpiperidine-1-oxy catalyst, and hypochlorite or hypobromite, while adjusting pH to fall within the range of 5-9, and further, extracting a nucleoside-carboxylic acid compound represented by the formula (2) into an organic solvent under acidic conditions, back-extracting the compound from the organic solvent into an aqueous alkali solution, and neutralizing the aqueous alkali solution by adding an acid thereto to allow precipitation of a crystal. Thus, a highly pure particular nucleoside-carboxylic acid compound or a salt thereof can be produced by a method suitable for industrial production: wherein each symbol is as defined in the Description.
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(2008/06/13)

The nucleoside transport proteins, NupC and NupG, from Escherichia coli: Specific structural motifs necessary for the binding of ligands
A series of 46 natural nucleosides and analogues (mainly adenosine-based) were tested as inhibitors of [U-14C]uridine uptake by the concentrative, H+-linked nucleoside transport proteins NupC and NupG from Escherichia coli. The two evolutionarily unrelated transporters showed similar but distinct patterns of inhibition, revealing differing selectivities for the different nucleosides and their analogues. Binding of nucleosides to NupG required the presence of hydroxyl groups at each of the C-3′ and C-5′ positions of ribose, while binding to NupC required only the C-3′ hydroxyl substituent. The greater importance of the ribose moiety for binding to NupG is consistent with the evolutionary relationship between this protein and the oligosaccharide: H+ symporter (OHS) subfamily of the major facilitator superfamily (MFS) of transporters. For both proteins the natural α-configuration at C-3′ and the natural β-configuration at C-1′ was mandatory for ligand binding. N-7 in the imidazole ring of adenosine and the amino group at C-6 were found not to be important for binding and both transporters showed flexibility for substitution at C-6/N6; one or both of N-l and N-3 were important for adenosine analogue binding to NupC but significantly less so for binding to NupG. From the different effects of 8-bromoadenosine on the two transporters it appears that adenosine selectively binds to NupC in an anti- rather than a syn-conformation, whereas NupG is less prescriptive. The pattern of inhibition of NupC by differing nucleoside analogues confirmed the functional relationship of the bacterial transporter to members of the human concentrative nucleoside transporter (CNT) family and reaffirmed the use of the bacterial protein as an experimental model for these physiologically and clinically important mammalian proteins. The specificity data for NupG have been used to develop a homology model of the protein's binding site, based on the X-ray crystallographic structure of the disaccharide transporter LacY from E. coli. We have also developed an efficient general protocol for the synthesis of adenosine and three of its analogues, which is illustrated by the synthesis of [1′-13C]adenosine.
Patching, Simon G.,Baldwin, Stephen A.,Baldwin, Alexander D.,Young, James D.,Gallagher, Maurice P.,Henderson, Peter J. F.,Herbert, Richard B.
p. 462 - 470
(2007/10/03)

IMPROVED SYNTHESIS OF 2-SUBSTITUTED ADENOSINES
A method of synthesis of a 2-substituted adenosine of formula I which comprises converting a compound of formula II to a compound of formula (I), wherein: R is C 1-6 alkoxy (straight or branched), a phenoxy group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, C 1-6 alkyl, or C 1-6 alkoxy), a benzyloxy group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, Cl_6 alkyl, or Cl_6 alkoxy), or a benzoyl group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, C 1-6 alkyl, or C 1-6 alkoxy); R' = H, or a protecting group.
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(2008/06/13)

Nucleic acid related compounds. 118. Nonaqueous diazotization of aminopurine derivatives. Convenient access to 6-halo- and 2,6-dihalopurine nucleosides and 2′-deoxynucleosides with acyl or silyl halides
Treatment of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloropurine (1) with TMS-Cl and benzyltriethylammonium nitrite (BTEA-NO2) in dichloromethane gave the crystalline 2,6-dichloropurine nucleoside 2, and acetyl chloride/BTEA-NO2 was equally effective (～85%, without chromatography). TMS-Br/tert-butyl nitrite/dibromomethane gave crystalline 2-bromo-6-chloro analogue 3 (85%). (Chloro or bromo)-dediazoniation of 3′,5′-di-O-acetyl-2′-deoxyadenosine (4) gave the 6-[chloro (5, 63%) or bromo (6, 80%)]purine deoxynucleosides, and 2′,3′,5′-tri-O-acetyladenosine (8) was converted into the 6-chloropurine nucleoside 9 (71%).
Francom, Paula,Robins, Morris J.
p. 666 - 669
(2007/10/03)

The Synthesis of 2′-O-[(Triisopropylsilyl)oxy] methyl (TOM) Phosphoramidites of Methylated Ribonucleosides (m1G, m2G, m22G, m1I, m3U, m4C, m6A, m62A) for Use in Automated RNA Solid-Phase Synthesis
The straightforward synthesis of eight methylated ribonucleoside phosphoramidites is described. These building blocks allow for incorporation of the naturally occuring nucleosides 1-methylguanosine (m1G), N 2-methylguanosine (m2G), N2N 2-dimethylguanosine (m22G), 1-methylinosine (m1I), 3-methyluridine (m3U), N4- methylcytidine (m4C), N6-methyladenosine (m6A), and N6,N6-dimethyladenosine (m62A) into oligoribonucleotides by automated RNA solid-phase synthesis. In all cases, the ribose 2′-hydroxyl group of the building blocks is masked by the recently introduced [(triisopropylsilyl)oxy]methyl (TOM) group.
Hoebartner, Claudia,Kreutz, Christoph,Flecker, Elke,Ottenschlaeger, Elke,Pils, Werner,Grubmayr, Karl,Micura, Ronald
p. 851 - 873
(2007/10/03)

Nucleic acid related compounds. 116. Nonaqueous diazotization of aminopurine nucleosides. Mechanistic considerations and efficient procedures with tert-butyl nitrite or sodium nitrite
Nonaqueous diazotization-dediazoniation of two types of aminopurine nucleoside derivatives has been investigated. Treatment of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloropurine (1) with SbCl3/CH2Cl2 was examined with benzyltriethylammonium (BTEA) chloride as a soluble halide source and tert-butyl nitrite (TBN) or sodium nitrite as the diazotization reagent. Optimized yields (>80%) of the 2,6-dichloropurine derivative were obtained with SbCl3. Combinations with SbBr3/CH2Br2 gave the 2-bromo-6-chloropurine product (>60%), and SbI3/CH2I2/THF gave the 2-iodo-6-chloropurine derivative (>45%). Antimony trihalide catalysis was highly beneficial. Mixed combinations (SbX3/CH2X′2; X/X′ = Bt/Cl) gave mixtures of 2-(bromo, chloro, and hydro)-6- chloropurine derivatives that were dependent on reaction conditions. Addition of iodoacetic acid (IAA) resulted in diversion of purine radical species into a 2-iodo-6-chloropurine derivative with commensurate loss of other radical-derived products. This allowed evaluation of the efficiency of SbX3-promoted cation-derived dediazoniations relative to radical-derived reactions. Efficient conversions of adenosine, 2′-deoxyadenosine, and related adenine nucleosides into 6-halopurine derivatives of current interest were developed with analogous combinations.
Francom, Paula,Janeba, Zlatko,Shibuya, Susumu,Robins, Morris J.
p. 6788 - 6796
(2007/10/03)

Microwave induced synthesis of ribonucleosides on solid support.
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Andrzejewska, Mariola,Kaminski, Jarosla,Kazimierczuk, Zygmunt
p. 73 - 78
(2007/10/03)

Prodrug azide compositions and compounds
Pharmaceutical prodrug compositions are provided comprising azide derivatives of drugs which are capable of being converted to the drug in vivo. Azide derivatives of drugs having amine, ketone and hydroxy substituents are converted in vivo to the corresponding drugs, increasing the half-life of the drugs. In addition azide prodrugs are often better able to penetrate the blood-brain barrier than the corresponding drugs. Especially useful are azide derivatives of cordycepin, 2′-F-ara-ddI, AraA, acyclovir, penciclovir and related drugs. Useful azide prodrugs are azide derivatives of therapeutic alicyclic amines, ketones, and hydroxy-substituted compounds, including aralkyl, heterocyclic aralkyl, and cyclic aliphatic compounds, where the amine or oxygen moiety is on the ring, or where the amine or oxygen moiety is on an aliphatic side chain, as well as therapeutic purines and pyrimidines, nucleoside analogs and phosphorylated nucleoside analogs.
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(2008/06/13)

Synthesis of isotopically labelled versions of adenosine agonist GR79236
Versions of adenosine receptor agonist GR79236, labelled either with carbon-14 at C-8 of the purine ring or with tritium in the cyclopentyl ring, were prepared in overall yields of 64% and 25% respectively. A mass labelled [M + 4] version containing carbon-13, nitrogen-15, and deuterium was also prepared in 3% yield.
Wadsworth, Alan H.,Newman, John J.,Wipperman, Mark D.,Fellows, Ian,Sutherland, Derek R.
p. 11 - 28
(2007/10/03)

The relation between the properties of polyclonal antibodies to (2′-5′)oligoadenylates and the mode of the hapten-immunogen conjugation
To elucidate the antibody-(2′-5′)oligoadenylate relation to the mode of the hapten-immunogen conjugation, a new (2′-5′)oligoadenylic acid trimer derivative containing a 2′-terminal N6(5-carboxypentyl)adenosine and its 125I-labeled immunogenic conjugate were synthesized. The immunization with this conjugate and with a conjugate based on the 2′,3′-O-[1-(2-carboxyethyl)]ethylidene derivative of the (2′-5′)triadenylic acid gave antisera with different affinities toward modified (2′-5′)oligonucleotides. Epitopes involved in the (2′-5′)oligomer-binding to different antisera were found.
Kulak,Kvasyuk,Sentyureva,Shulyakovskaya,Matyushevskaya,Makarenko,Mikhailopulo
p. 603 - 611
(2007/10/03)

Diimidazo[1,2-c:4',5'-e]pyrimidines: N6-N1 conformationally restricted adenosines
Tethering the N6-substituents of N6-substituted adenosines to N1 has resulted in a series of conformationally restricted adenosine analogues. The resultant diimidazo[1,2-c:4',5'-e]pyrimidines were shown to be adenosine A1 selective.
Camp, David,Li, Ying,McCluskey, Adam,Moni, Roger W.,Quinn, Ronald J.
p. 695 - 698
(2007/10/03)

Synthesis, biotransformation, and pharmacokinetic studies of 9-(β-D- arabinofuranosyl)-6-azidopurine: A prodrug for ara-A designed to utilize the azide reduction pathway
As a part of our efforts to design prodrugs for antiviral nucleosides, 9-(β-D-arabinofuranosyl)-6-azidopurine (6-AAP) was synthesized as a prodrug for ara-A that utilizes the azide reduction biotransformation pathway. 6-AAP was synthesized from ara-A via its 6-chloro analogue 4. The bioconversion of the prodrug was investigated in vitro and in vivo, and the pharmacokinetic parameters were determined. For in vitro studies, 6-AAP was incubated in mouse serum and liver and brain homogenates. The half-lives of 6-AAP in serum and liver and brain homogenates were 3.73, 4.90, and 7.29 h, respectively. 6- AAP was metabolized primarily in the liver homogenate microsomal fraction by the reduction of the azido moiety to the amine, yielding ara-A. However, 6- AAP was found to be stable to adenosine deaminase in a separate in vitro study. The in vivo metabolism and disposition of ara-A and 6-AAP were conducted in mice. When 6-AAP was administered by either oral or intravenous route, the half-life of ara-A was 7-14 times higher than for ara-A administered intravenously. Ara-A could not be found in the brain after the intravenous administration of ara-A. However, after 6-AAP administration (by either oral or intravenous route), significant levels of ara-A were found in the brain. The results of this study demonstrate that 6-AAP is converted to ara-A, potentially increasing the half-life and the brain delivery of ara-A. Further studies to utilize the azide reduction approach on other clinically useful agents containing an amino group are in progress in our laboratories.
Kotra,Manouilov,Cretton-Scott,Sommadossi,Boudinot,Schinazi,Chu
p. 5202 - 5207
(2007/10/03)

ORGANIC SYNTHESIS USING ORGANOSULFUR-NITRITES AND -NITRATES
Thionitrites or thionitrates have been considered to be unstable.However, bulky groups' thio-NOn such as t-butylthio-nitrites and -nitrates have been readily synthesized and found to be stable enough for the use of the useful organic syntheses as an excellent nitrosation and diazotization reagents under mild conditions.Direct conversion of amines to the corresponding halides in the presence of copper halides (II), fluorination of heterocyclic amines in the presence of sodium tetrafluoroborate, α- oximation of methylene groups in ketones, facile cleavage of C=N bond to ketones, and desulfurization of thioacetals and thioketals, and other useful organic syntheses are described.
Kim, Yong Hae
p. 249 - 260
(2007/10/02)

Nucleosides and nucleotides. 103. 2-Alkynyladenosines: A novel class of selective adenosine A2 receptor agonists with potent antihypertensive effects
The synthesis and receptor-binding activities at A1 and A2 adenosine receptors for a series of 2-alkynyladenosines are described. The palladium- catalyzed cross-coupling reaction of 2-iodoadenosine (4a) with various terminal alkynes
Matsuda,Shinozaki,Yamaguchi,Homma,Nomoto,Miyasaka,Watanabe,Abiru
p. 241 - 252
(2007/10/02)

Methods of making novel R and S diastereomers of N6 -[(2-hydroxypropyl)aryl]adenosines
A method of making novel R and S diastereomers of an N6 -[(2-hydroxypropyl)aryl] adenosine, which diastereomers exhibit fewer CNS side effects than the racemate, but with no decrease in cardiovascular activity.
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(2008/06/13)

An Unambiguous Synthesis of Adenylosuccinic Acid and its Constituent Nucleoside
6-(4-Chlorophenylthio)-9-(2,3-O-cyclopentylidene-β-D-ribofuranosyl)-9H-purine (7) is prepared from 6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine (5) in three steps and is then converted, by treatment with 3-chloroperbenzoic acid, into the corresponding sulphoxide (9) and crystalline sulphone (8) in ca. 88 and 65percent isolated yield, respectively.When the sulphoxide (9) is heated with dibenzyl L-aspartate in N,N-dimethylacetamide solution at 70-75 deg C for 28 hr, compound (11) is obtained in ca. 70percent isolated yield.Removal of the protecting groups from compound (11) gives N--L-aspartic acid (3) as a crystalline solid in ca. 68percent yield; phosphorylation of compound (11) with dibenzyl phosphorochloridate and removal of the protecting groups gives adenylosuccinic acid (1), isolated as its ammonium salt, in ca. 66percent yield.When the sulphone (8) is converted via compound (11) into the diacids (3) and (1), the products obtained appear to be contaminated with the D-acids (12) and (14), respectively, which are diastereomers of compounds (3) and (1).
Buck, Ildiko M.,Reese, Colin B.
p. 2937 - 2942
(2007/10/02)

Nucleic Acid Related Compounds. 48. Photoaddition of Methanol to 9-(β-D-Ribofuranosyl)purine (Nebularine) To Give Inhibitors of Adenosine Deaminase
Photolysis of anaerobic solutions of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (2',3',5'-tri-O-acetylnebularine) (1b) in methanol at 2537 Angstroem gave a diastereomeric mixture of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,6-dihydro-6(R,S)-(hydroxymethyl)purines (2b) plus secondary photoproducts.The presence of oxygen resulted in more rapid formation of the 6-(hydroxymethyl)- (3b), 1,6-dihydro-6,6-bis(hydroxymethyl)- (4b), 6-methyl- (5b), and (R,S)-1,6-dihydro-6-(hydroxymethyl)-6-methyl-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (6b) byproducts.Reevaluation of recently published claims that photoaddition of methanol to nebularine proceeded with high stereoselectivity is presented based on definitive 1H and 13C NMR spectral data and FAB mass spectrometry.
Buffel, Diederik K.,McGuigan, Christopher,Robins, Morris J.
p. 2664 - 2667
(2007/10/02)

Dog Coronary Artery Adenosine Receptor: Structure of the N6-Alkyl Subregion
The moderately potent and stereoselective coronary vasoactivity of N6-adenosine (1) is the basis for the present study that maps the N6 region of the coronary artery adenosine receptor by means of the structure-coronary vasoactivity relationships of 81 analogues of 1 in the open-thorax dog.Stereoselectivity is a general property of N6-substituted adenosines that have a chiral center adjacent to N6.The activity ratio of 1 to its S diastereomer is 10, the result of the positive interaction with the receptor of the propyl C-3 group of the Rdiastereomer in combination with the steric hindrance exerted by this group of the S diastereomer.Replacing the benzyl moiety of 1 by an ethyl, phenyl, phenethyl, or naphthyl group lowers potency of the R diastereomer and, accordingly, the R/S ratio.Propyl C-1 interacts with a receptor region large enough to accommodate three methylene residues and the propyl C-3 residue with a separate region large enough to accommodate two.The receptor subregion that interacts with the propyl C-1 of 1 is more tolerant of bulk and of polar substituents than the subregion that interacts with propyl C-3.Evidence bearing on the possible contribution of N6 to activity, e.g. through hydrogen bonding, is ambiguous.These results support a provisional model of the N6-alkyl subregion.
Kusachi, Shozo,Thompson, Robert D.,Bugni, William J.,Yamada, Nobuyuki,Olsson, R. A.
p. 1636 - 1643
(2007/10/02)

Conformational studies of some carbocyclic nucleoside analogues
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Legraverend,Lhoste,Bisagni
p. 709 - 713
(2007/10/02)

Syntheses of 9-β-D-Ribofuranosylpurine (Nebularine) and Its Analogues
9-β-D-Ribofuranosylpurine (nebularine) (9) has been synthesized by two methods. (i) 2,6-Dichloro-2',3',5'-tri-O-benzoyl-9-β-D-ribofuranosylpurine (7) on dehalogenation followed by debenzoylation using methanolic ammonia affords nebularine (9). (ii) 6-Chloro-2',3',5'-tri-O-acetyl-9-β-D-ribofuranosylpurine (18) on dehalogenation followed by deacetylation yields 9.Nebularine analogues , 9-β-D-xylofuranosylpurine (12) and 9-α-L-rhamnopyranosylpurine (15) have also been synthesized from 2,6-dichloro-2',3',5'-tri-O-acetyl-9-β-D-xylofuranosylpurine (10) and 2,6-dichloro-2',3',4'-tri-O-benzoyl-9-α-L-rhamnopyranosylpurine (13).Dehalogenation of 10 and 13 followed by deacetylation and debenzoylation with methanolic ammonia affords 12 and 15 respectively.
Gupta, P. K.,Bhakuni, D. S.
p. 534 - 537
(2007/10/02)

Riburonic and Lyxuronic Purine Nucleoside Derivatives - Synthesis, Separation, and Structural Elucidation of the Various Linkage Isomers
By direct, molten state condensation of riburonic (1) and lyxuronic acid derivatives (14) with silylated purine (2a), chloro- and amino-purines (2b-g), respectively, N-7 and N-9 purinyl nucleosides with both α- and β-configuration were obtained in mixtures of varying composition, depending, inter alia, on the structure of the carboxyl function; the linkage isomers were separated quantitatively by medium pressure chromatography on silica gel columns of high separation potential.To test the known criteria for structural assignment on the wide range of glycosidic isomers thus available, UV, 1H-NMR and 13C-NMR spectra were recorded under standardized conditions for all derivatives.Assignment of purine regiochemistry from UV data proved not reliable; it can be established, though, unequivocally from the 13C-NMR data of the aglycone.The configuration at the anomeric center of the sugar mioety, on the other hand, is readily determined from the furanoside 13C-shifts of the 2',3'-O-isopropylidenated nucleosides.
Schmidt, Richard R.,Loesch, Gabriele R.,Fischer, Peter
p. 2891 - 2915
(2007/10/02)

Utility of Purinyl Radicals in the Synthesis of Base-Modified Nucleosides and Alkylpurines: 6-Amino Group Replacement by H, Cl, Br, and I
When 9-substituted adenines are treated with n-pentyl nitrite in hydrogen atom donating solvents and the resulting reaction mixtures are warmed and photolyzed with visible light, the corresponding 9-substituted purines are isolated.The conversion apparently involves homolysis of the intermediate 6-diazonium salts or azo compounds to produce purinyl radical intermediates.These purinyl radicals can subsequently abstract hydrogen atoms from solvent molecules.We have utilized our deamination procedure for the direct synthesis of the antitumor antibiotic nebularine from adenosine.When the deaminations of 9-substituted adenines are conducted in dry CCl4, CHBr3, or CH2I2, the corresponding 6-chloro-, 6-bromo-, and 6-iodopurines are isolated in good yields.There appears to be no detectable hydrogen abstraction in competition with halogen abstraction in the cases of CHBr3 and CH2I2 solvents.These transformations provide shortened preparative pathways to intermediates useful in the synthesis of other base-modified purines.Under appropriate reaction conditions, conversions to the 6-6' dimers also may be possible.The type of transformation in this report represents one of the first examples of the use of neutral purinyl radicals in nucleic acid chemistry.
Nair, Vasu,Richardson, Stephen G.
p. 3969 - 3974
(2007/10/02)