- Reaction of O6-methylguanosine with nitrite in the presence of carboxylic acid: Synthesis of the purin-2-yl carboxylate
-
O6-Methylguanosine derivative was treated with sodium nitrite or isoamylnitrite in the presence of carboxylic acid to give the purin-2-yl carboxylate, an unusual product bearing a carboxylic group at the 2-position of the purine moiety.
- Maruyama, Tokumi,Moriwaka, Nobuyasu,Demizu, Yosuke,Ohtsuka, Masami
-
-
Read Online
- Intermediate for synthesizing 2-chloroadenosine, synthesis process of intermediate and synthesis process of 2-chloroadenosine
-
The invention relates to the technical field of organic synthesis, in particular to an intermediate for synthesizing 2-chloroadenosine, a synthesis process of the intermediate and a synthesis processof the 2-chloroadenosine. The synthesis process of the intermediate for synthesizing the 2-chloroadenosine comprises the following step: carrying out condensation reaction on 2,6-dichloropurine and tetraacetylribose under the catalytic action of 4-dimethylaminopyridine to form 2,3,5-4-triacetyl-2,6-dichloropurine riboside. The synthesis process is simple to operate, low in catalyst dosage, low incost, low in pollution and easy to industrially implement, and the yield and purity of the synthesized 2-chloroadenosine are higher.
- -
-
Paragraph 0051-0052; 0057-0059; 0060-0068
(2021/01/25)
-
- 2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
-
CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
- Bhattarai, Sanjay,Pippel, Jan,Scaletti, Emma,Idris, Riham,Freundlieb, Marianne,Rolshoven, Georg,Renn, Christian,Lee, Sang-Yong,Abdelrahman, Aliaa,Zimmermann, Herbert,El-Tayeb, Ali,Müller, Christa E.,Str?ter, Norbert
-
p. 2941 - 2957
(2020/04/10)
-
- Synthesis of novel 6-substituted amino-9-(β-D-ribofuranosyl)purine analogs and their bioactivities on human epithelial cancer cells
-
New nucleoside derivatives with nitrogen substitution at the C-6 position were prepared and screened initially for their in vitro anticancer bioactivity against human epithelial cancer cells (liver Huh7, colon HCT116, breast MCF7) by the NCI-sulforhodamine B assay. N6-(4-trifluoromethylphenyl)piperazine analog (27) exhibited promising cytotoxic activity. The compound 27 was more cytotoxic (IC50 = 1–4 μM) than 5-FU, fludarabine on Huh7, HCT116 and MCF7 cell lines. The most potent nucleosides (11, 13, 16, 18, 19, 21, 27, 28) were further screened for their cytotoxicity in hepatocellular cancer cell lines. The compound 27 demonstrated the highest cytotoxic activity against Huh7, Mahlavu and FOCUS cells (IC50 = 1, 3 and 1 μM respectively). Physicochemical properties, drug-likeness, and drug score profiles of the molecules showed that they are estimated to be orally bioavailable. The results pointed that the novel derivatives would be potential drug candidates.
- Tuncbilek, Meral,Kucukdumlu, Asl?gul,Guven, Ebru Bilget,Altiparmak, Duygu,Cetin-Atalay, Rengul
-
supporting information
p. 235 - 239
(2018/02/15)
-
- Base-modified GDP-mannose derivatives and their substrate activity towards a yeast mannosyltransferase
-
We have previously developed a new class of inhibitors and chemical probes for glycosyltransferases through base-modification of the sugar-nucleotide donor. The key feature of these donor analogues is the presence of an additional substituent at the nucleobase. To date, the application of this general concept has been limited to UDP-sugars and UDP-sugar-dependent glycosyltransferases. Herein, we report for the first time the application of our approach to a GDP-mannose-dependent mannosyltransferase. We have prepared four GDP-mannose derivatives with an additional substituent at either position 6 or 8 of the nucleobase. These donor analogues were recognised as donor substrates by the mannosyltransferase Kre2p from yeast, albeit with significantly lower turnover rates than the natural donor GDP-mannose. The presence of the additional substituent also redirected enzyme activity from glycosyl transfer to donor hydrolysis. Taken together, our results suggest that modification of the donor nucleobase is, in principle, a viable strategy for probe and inhibitor development against GDP-mannose-dependent GTs.
- Collier, Alice,Wagner, Gerd K.
-
-
- CHEMO-ENZYMATIC PREPARATION METHOD FOR PURINE NUCLEOSIDES AND THEIR DEAZA- AND AZA- ANALOGUES
-
The present invention relates to a new, chemo-enzymatic preparation method of purine nucleosides and their deaza- and aza analogues of general formula I or pharmaceutically acceptable esters or salts thereof (I) wherein X, Y, Z and V independently from each other represent a nitrogen or carbon atom, W represents a nitrogen atom, -CH, -CF or –C-NH2, R1 represents hydrogen, fluorine (ribo/arabino), -OH (ribo/arabino) or -NH2 (ribo), R 2 represents -OH, -NH 2 or hydrogen,and Sub 2 and Sub 6 represent hydrogen, chlorine, fluorine, bromine or -NH 2, wherein at least one of Sub 2 and Sub 6 is -NH2.
- -
-
Page/Page column 13
(2016/03/19)
-
- Direct One-Pot Synthesis of Nucleosides from Unprotected or 5-O-Monoprotected d -Ribose
-
New, improved methods to access nucleosides are of general interest not only to organic chemists but to the greater scientific community as a whole due their key implications in life and disease. Current synthetic methods involve multistep procedures employing protected sugars in the glycosylation of nucleobases. Using modified Mitsunobu conditions, we report on the first direct glycosylation of purine and pyrimidine nucleobases with unprotected d-ribose to provide β-pyranosyl nucleosides and a one-pot strategy to yield β-furanosides from the heterocycle and 5-O-monoprotected d-ribose.
- Downey, A. Michael,Richter, Celin,Pohl, Radek,Mahrwald, Rainer,Hocek, Michal
-
p. 4604 - 4607
(2015/09/28)
-
- Synthesis and anti-HIV activity of a series of 6-modified 2′,3′-dideoxyguanosine and 2′,3′-didehydro-2′, 3′-dideoxyguanosine analogs
-
In search of potential 2′,3′-dideoxyguanosine (ddG) and 2′,3′-didehydro-2′,3′-dideoxyguanosine (D4G) prodrugs, a series of 6-modified ddG, D4G analogs were synthesized and evaluated for their anti-HIV activities and cytotoxities in cell-based assays. All analogs showed low cytotoxicities and some of them displayed benign anti-HIV activities. The active triphosphate forms in vivo, ddGTP and D4TTP, were also synthesized by a novel and facile one-pot method. The recognition of ddGTP and D4TTP by Taq, Therminater DNA polymerase and HIV reverse transcriptase (RT) incorporated in DNA/RNA strands were investigated by a non-radioactivity method and K m were determined. A series of 6-modified 2′,3′- dideoxyguanosine and 2′,3′-didehydro-2′,3′- dideoxyguanosine analogs were synthesized. Anti-HIV activity was investigated in cell-based assay. ddGTP was synthesized as well as D4TTP by a novel one-pot method, and the incorporation efficiencies recognized by DNA polymerase and HIV reverse transcriptase (HIV RT) were evaluated. Copyright
- Xie, Lujia,Yang, Xiantao,Pan, Delin,Cao, Yingli,Cao, Mou,Lin, Guichun,Guan, Zhu,Guo, Ying,Zhang, Lihe,Yang, Zhenjun
-
p. 1207 - 1218
(2013/10/21)
-
- Production, characterization and synthetic application of a purine nucleoside phosphorylase from Aeromonas hydrophila
-
Purine nucleoside phosphorylase (PNP) from Aeromonas hydrophila encoded by the deoD gene has been over-expressed in Escherichia coli, purified, characterized about its substrate specificity and used for the preparative synthesis of some 6-substituted purine-9-ribosides. Substrate specificity towards natural nucleosides showed that this PNP catalyzes the phosphorolysis of both 6-oxo- and 6-aminopurine (deoxy)ribonucleosides. A library of nucleoside analogues was synthesized and then submitted to enzymatic phosphorolysis as well. This assay revealed that 1-, 2-, 6- and 7-modified nucleosides are accepted as substrates, whereas 8-substituted nucleosides are not. A few transglycosylation reactions were carried out using 7-methylguanosine iodide (4) as a d-ribose donor and 6-substituted purines as acceptor. In particular, following this approach, 2- amino-6-chloropurine-9-riboside (2c), 6-methoxypurine- 9-riboside (2d) and 2-amino-6-(methylthio)purine- 9-riboside (2g) were synthesized in very high yield and purity.
- Ubiali, Daniela,Serra, Carla D.,Serra, Immacolata,Morelli, Carlo F.,Terreni, Marco,Albertini, Alessandra M.,Manitto, Paolo,Speranzab, Giovanna
-
experimental part
p. 96 - 104
(2012/04/11)
-
- Evidence for the existence of a specific gprotein-coupled receptor activated by guanosine
-
Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5'-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a Gprotein-coupled receptor that is different from the well-characterized adenosine receptors. Catching the elusive guanosine receptor: The innovative DELFIA Eu-GTP binding assay was applied to characterize the guanosine binding site by using novel and known guanosine derivatives. Some of the tested compounds, which proved to be full agonists with EC50 values in the low nanomolar range, could be useful tools for further characterization of the putative guanosine receptor.
- Volpini, Rosaria,Marucci, Gabriella,Buccioni, Michela,DalBen, Diego,Lambertucci, Catia,Lammi, Carmen,Mishra, Ram C.,Thomas, Ajiroghene,Cristalli, Gloria
-
p. 1074 - 1080
(2012/01/06)
-
- Aeromonas hydrophila strains as biocatalysts for transglycosylation
-
Microbial transglycosylation is useful as a green alternative in the preparation of purine nucleosides and analogues, especially for those that display pharmacological activities. In a search for new transglycosylation biocatalysts, two Aeromonas hydrophila strains were selected. The substrate specificity of both micro-organisms was studied and, as a result, several nucleoside analogues have been prepared. Among them, ribavirin, a broad spectrum antiviral, and the well-known anti HIV didanosine, were prepared, in 77 and 62% yield using A. hydrophila CECT 4226 and A. hydrophila CECT 4221, respectively. In order to scale-up the processes, the reaction conditions, product purification and biocatalyst preparation were analyzed and optimized.
- Nbile, Matas,Terreni, Marco,Lewkowicz, Elizabeth,Iribarren, Adolfo M.
-
experimental part
p. 395 - 402
(2011/10/08)
-
- Chemoenzymatic preparation of nucleosides from furanoses
-
Chemoenzymatic preparation of ribose, deoxyribose and arabinose 5-phosphates was accomplished. These compounds were tested as starting materials in the enzymatic preparation of natural and modified purine and pyrimidine nucleosides, using an overexpressed Escherichia coli phosphopentomutase.
- Taverna-Porro, Marisa,Bouvier, Leon A.,Pereira, Claudio A.,Montserrat, Javier M.,Iribarren, Adolfo M.
-
p. 2642 - 2645
(2008/09/19)
-
- High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries
-
The Vorbrueggen glycosylation reaction was adapted into a one-step 5 min/130 °C microwave assisted reaction. Triethanolamine in acetontrile containing 2% water was determined to be optimal for the neutralization of trimethylsilyl inflate allowing for direct MPLC purification of the reaction mixture. When coupled with a NH3/methanol deprotection reaction, a high-throughput method of nucleoside library synthesis was enabled. The method was demonstrated by examining the ribosylation of 48 nitrogen containing heteroaromatic bases that included 25 purines, four pyrazolopyrimidines, two 8-azapurines, one 2-azapurine, two imidazopyridines, two benzimidazoles, three imidazoles, three 1,2,4-triazoles, two pyrimidines, two 3-deazapyrimidines, one quinazolinedione, and one alloxazine. Of these, 32 yielded single regioisomer products, and six resulted in separable mixtures. Seven examples provided inseparable regioisomer mixtures of -two to three compounds (16 nucleosides), and three examples failed to yield isolable products. For the 45 single isomers isolated, the average two-step overall yield ± SD was 26 ± 16%, and the average purity ± SD was 95 ± 6%. A total of 58 different nucleosides were prepared of which 15 had not previously been accessed directly from glycosylation/deprotection of a readily available base.
- Bookser, Brett C.,Raffaele, Nicholas B.
-
p. 173 - 179
(2007/10/03)
-
- Anti-HCV nucleoside derivatives
-
The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
- -
-
-
- Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
-
The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
- -
-
-
- Reaction of arylnitrenium ions with guanine derivatives: N1-methylguanosine and N2,N2-dimethylguanosine
-
A prior flash photolysis study of the direct reaction of arylnitrenium ions with 2′-deoxyguanosine identified a second intermediate that grew in as the transient nitrenium ion reacted with the nucleoside. This intermediate was identified as the the product of the addition of the nitrenium ion to the C-8 position of guanine prior to loss of the C-8 proton - the C-8 intermediate. A feature of the C-8 intermediate is that it exists in acid-base forms. This behavior was evident in both a spectroscopic analysis as well as in the rate-pH profile, which showed a break around pH 4 from a pH-independent reaction to a reaction that was first-order in H+. The present study was designed to identify the structure of the conjugate base form. This involved a kinetic study of the decay of the C-8 intermediate derived from the reaction of the 2-fluorenylnitrenium ion with N1-methylguanosine and N2,N2-dimethylguanosine. The rationale was that the former is unable to lose the N-1 proton, while the latter cannot deprotonate at the NH2 group. The rate-pH profiles clearly show that it is the N-1 proton that is acidic. The rate constants for the C-8 intermediate of N2,N2-dimethylguanosine show the same downward break observed with 2′-deoxyguanosine and guanosine associated with conversion to the conjugate base form. In contrast, the rate constants for the N1-methylguanosine intermediate are independent of pH. Rate constants for the reaction forming the C-8 intermediate are also reported. These show that the reaction of nitrenium ions with the N2,N2-dimethylguanine derivative is significantly faster (except where the reactions are diffusion controlled). This is consistent with the initial step of the reaction of an arylnitrenium ion and guanine occurring by direct addition at C-8. The developing positive charge in such a reaction can be delocalized to the C-2 position where π donors such as NH2 and NMe2 can exert a stabilizing effect.
- Cheng, Bernice,McClelland, Robert A.
-
p. 1881 - 1886
(2007/10/03)
-
- REMOVAL OF SILYL PROTECTING GROUPS FROM HYDROXYL FUNCTIONS WITH AMMONIUM FLUORIDE IN METHANOL
-
Treatment of silyl ethers with excess ammonium fluoride in methanol at 60 deg C effected cleavage to alcohols within 5 hours.Deprotection at ambient temperature required 1-2 days.NH4F/MeOH is an economical alternative to TBAF/THF.
- Zhang, Weijian,Robins, Morris J.
-
p. 1177 - 1180
(2007/10/02)
-
