- Synthetic (p)ppGpp analogue is an inhibitor of stringent response in mycobacteria
-
Bacteria elicit an adaptive response against hostile conditions such as starvation and other kinds of stresses. Their ability to survive such conditions depends, in part, on stringent response pathways. (p)ppGpp, considered to be the master regulator of t
- Syal, Kirtimaan,Flentie, Kelly,Bhardwaj, Neerupma,Maiti, Krishnagopal,Jayaraman, Narayanaswamy,Stallings, Christina L.,Chatterji, Dipankar
-
-
Read Online
- 2′-Modified Guanosine Analogs for the Treatment of HCV
-
Novel 2′-modified guanosine nucleosides were synthesized from inexpensive starting materials in 7–10 steps via hydroazidation or hydrocyanation reactions of the corresponding 2′-olefin. The antiviral effectiveness of the guanosine nucleosides was evaluated by converting them to the corresponding 5′-O-triphosphates (compounds 38–44) and testing their biochemical inhibitory activity against the wild-type NS5B polymerase.
- Girijavallabhan, Vinay,Arasappan, Ashok,Bennett, Frank,Chen, Kevin,Dang, Qun,Huang, Ying,Kerekes, Angela,Nair, Latha,Pissarnitski, Dmitri,Verma, Vishal,Alvarez, Carmen,Chen, Ping,Cole, David,Esposite, Sara,Huang, Yuhua,Hong, Qingmei,Liu, Zhidan,Pan, Weidong,Pu, Haiyan,Rossman, Randall,Truong, Quang,Vibulbhan, Bancha,Wang, Jun,Zhao, Zhiqiang,Olsen, David,Stamford, Andrew,Bogen, Stephane,Njoroge, F. George
-
p. 277 - 294
(2016/07/06)
-
- 2'-CYANO SUBSTITUTED NUCLEOSIDE DERIVATIVES AND METHODS OF USE THEREOF USEFUL FOR THE TREATMENT OF VIRAL DISEASES
-
The present invention relates to 2′-Cyano Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, R1, R2 and R3 are as defined herein. The present invention also relates to compositions comprising at least one 2′-Cyano Substituted Nucleoside Derivative, and methods of using the 2′-Cyano Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.
- -
-
Paragraph 0232
(2014/06/24)
-
- 2'-AZIDO SUBSTITUTED NUCLEOSIDE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
-
The present invention relates to 2′-Azido Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, R1, R2 and R3 are as defined herein. The present invention also relates to compositions comprising at least one 2′-Azido Substituted Nucleoside Derivative, and methods of using the 2′-Azido Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.
- -
-
Paragraph 0241; 0242
(2014/08/06)
-
- 2'-SUBSTITUTED NUCLEOSIDE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
-
The present invention relates to 2'-Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, X, R1, R2 and R3 are as defined herein. The present invention also relates
- -
-
Page/Page column 57-58
(2012/11/06)
-
- Nucleobase and ribose modifications control immunostimulation by a MicroRNA-122-mimetic RNA
-
Immune stimulation is a significant hurdle in the development of effective and safe RNA interference therapeutics. Here, we address this problem in the context of a mimic of microRNA-122 by employing novel nucleobase and known 2′-ribose modifications. The
- Peacock, Hayden,Fucini, Raymond V.,Jayalath, Prasanna,Ibarra-Soza, Jose M.,Haringsma, Henry J.,Flanagan, W. Michael,Willingham, Aarron,Beal, Peter A.
-
supporting information; scheme or table
p. 9200 - 9203
(2011/08/04)
-
- Kinetics and mechanism of the defluorination of 8-fluoropurine nucleosides in basic and acidic media
-
For investigating the stability of C(8)-fluorine bond in 8-fluoropurine nucleosides some protected 8-fluoroguanosine, 8-fluoroinosine and 8-fluoroadenosine derivatives were prepared by direct fluorination of acetyl-protected purine nucleosides with elemental fluorine in solvents such as chloroform, acetonitrile and nitromethane. Fluorination reactions conducted in chloroform medium gave better yields of 8-fluoropurines. The fluorination yields were slightly lower when acetonitrile or nitromethane was used as solvent, but the product purification was found to be much easier. When the synthesized, protected fluoronucleosides were subjected to standard basic (NH3 in methanol or 2-propanol) and acidic (HCl in methanol) deprotection conditions relevant to nucleoside chemistry, an efficient defluorination reaction took place. The kinetics of these defluorination reactions were conveniently followed, under pseudo-first-order reaction conditions, using 19F NMR spectroscopy. 1H NMR, LC-MS and mass spectroscopy identified the products of the kinetic reaction mixtures. The defluorination reaction rate constants (kobs) in basic media depended upon the electron density at C(8) while the kobs data in acidic medium were determined by the pKa of N7. An addition-elimination based mechanism (SNAr) has been proposed for the defluorination reactions of these 8-fluoropurine nucleosides.
- Liu, Jie,Barrio, Jorge R.,Satyamurthy, Nagichettiar
-
p. 1175 - 1187
(2008/12/20)
-
- Reliable chemical synthesis of oligoribonucleotides (RNA) with 2′-O-[(triisopropylsilyl)oxy]methyl(2′-O-tom)-protected phosphoramidites
-
A method for the introduction of the 2′-O-[(triisopropylsilyl)oxy]methyl (=tom) group into N-acetylated, 5′-O-dimethoxytritylated ribonucleosides is presented. The corresponding 2′-O-tom-protected phosphoramidite building blocks were obtained in pure form and were successfully employed for the routine synthesis of oligoribonucleotides on DNA synthesizers. Under DNA coupling conditions (2.5 min coupling time for a 1.5-μmol synthesis scale) and with 5-(benzylthio)-1H-tetrazole (BTT) as activator, 2′-O-tom-protected phosphoramidites exhibited average coupling yields >99.4%. The combination of N-acetyl and 2′-O-tom protecting groups allowed a reliable and complete two-step deprotection, first with MeNH2 in EtOH/H2O and then with Bu4NF in THF, without concomitant destruction of the product RNA sequences.
- Pitsch, Stefan,Weiss, Patrick A.,Jenny, Luzi,Stutz, Alfred,Wu, Xiaolin
-
p. 3773 - 3795
(2007/10/03)
-
- Selective cleavage of the O6-diphenylcarbamoyl group from sugar-modified guanosines for incorporation into oligo-RNA
-
A facile conversion of 2',3',5'-O-tri-(Bz, Tol or Ac)-N2-(Ac or iBu)-O6-DPC-guanosine to N2-(Ac or iBu)-guanosine has been achieved in 89-98% yield by short treatment with 90% aqueous TFA for smooth cleavage of the DPC gro
- Foeldesi, Andras,Trifonova, Anna,Dinya, Zoltan,Chattopadhyaya, Jyoti
-
p. 7283 - 7284
(2007/10/03)
-
- Purine nucleoside analogues. 8*. N2-acetylation of guanine derivatives
-
A method for the acetylation of the exocyclic amino group of guanine derivatives has been developed. A series of N2-acetylguanines was synthesized by reacting of N9(7)-alkoxyalkylguanines with an excess of acetic anhydride in the pre
- Madre,Zhuk,Golankiewicz
-
p. 2242 - 2246
(2007/10/03)
-
- Regioselectivity and mechanism of transpurination reactions in the guanine nucleosides series
-
The transpurination reaction of the fully acetylated derivatives of guanosine and its 7-β-D-ribofuranosyl regioisomer with 2-acetoxyethyl acetoxymethyl ether has been studied using high performance liquid chromatography (HPLC). The regioselectivity of glycosyl exchange observed in the early stages of the reaction suggests that the unsubstituted nitrogen atoms of the imidazole portion (N7 and N9) are, exclusively, sites of direct glycosylation in the case of guanine derivatives. The results lead to the conclusion that the mechanism of the glycosylation reaction of guanine is different to that of adenine.
- Boryski, Jerzy
-
p. 649 - 652
(2007/10/03)
-
- Nucleic acid related compounds. 93. A solution for the historic problem of regioselective sugar-base coupling to produce 9-glycosylguanines or 7-glycosylguanines
-
Per(trimethylsilyl)-2-N-acylguanine derivatives and tetra-O-acylpentofuranoses were coupled [tin(IV) chloride or titanium(IV) chloride catalysis] to give predominant formation of 7-glycosylguanines. With TiCl4, a fortuitous organic/aqueous partitioning allowed isolation of 7-glycosylguanines from the 7/9 isomer mixtures. Per(trimethylsilyl)-2-N-acyl-6-O-(diphenylcarbamoyl)guanine derivatives and tetra-O-acylpentofuranoses underwent regioselective coupling (trimethylsilyl trifluoromethanesulfonate catalysis) to give 9-glycosylguanines. The 6-O-(diphenylcarbamoyl)peracyl-9-β-D-ribofuranosyl isomer was shown to be both the xinetic and thermodynamic coupling product. Deprotection of all of the peracyl coupling products was effected under mild conditions to give good to high yields of guanine nucleoside analogues. These methodologies provide solutions for the regioselective synthesis of 7- and 9-glycosylguanine nucleosides.
- Robins, Morris J.,Zou, Ruiming,Guo, Zhiqiang,Wnuk, Stanislaw F.
-
p. 9207 - 9212
(2007/10/03)
-
- Ozonation of thionucleosides. A new chemical transformation of 4-thiouracil and 6-thioguanine nucleosides to cytosine and adenosine counterparts
-
The ozonation of 4-thiopyrimidine and 6-thiopurine nucleosides in presence of amines afforded selectively and under mild experimental conditions several cytidine and adenosine nucleosides. The same reaction carried out in presence of alcohols afforded O4- or O6-alkylated derivatives of the nucleosides.
- Saladino, Raffaele,Crestini, Claudia,Occhionero, Francesca,Nicoletti, Rosario
-
p. 3607 - 3616
(2007/10/02)
-
- Tautomerism and regioselectivity in ribosylation of guanine
-
N2-acetyl- and 9,N2-diacetylguanines were subjected to reaction with tetraacetylribose in the presence of p-toluenesulfonic acid. Unlike the ribosylation of diacetylguanine, which gives 7-riboside as a kinetic product, the reaction of monoacetylguanine produces directly a mixture of 7- and 9-ribosides. This reflects N7H right arrow-left arrow N9H tautomerism of the guanine substrate and supports the hypothesis that only the unsubstituted nitrogens of the imidazolium portion of guanine (either N7 or N9) react directly with a sugar cation.
- Boryski,Manikowski
-
p. 287 - 290
(2007/10/02)
-
- Dimethyldioxirane oxidations: A new and efficient desulfurization of thiopyrimidine and thiopurine nucleosides
-
Dimethyldioxirane reacts with 2',3',5'-tri-O-acetyl-4(3H)thiouridine 1 and 2-acetamido-6-thio-9-(2',3',5'-tri-O-acetyl-β-d-ribosyl)purine 2 to afford several interesting desulfurized products.
- Crestini,Saladino,Bernini,Mincione
-
p. 7785 - 7788
(2007/10/02)
-
- Modification of the amino group of guanosine by methylglyoxal and other α-ketoaldehydes in the presence of hydrogen peroxide
-
Methylglyoxal is directly mutagenic to Salmonella typhimurium TA100 and its mutagenicity is markedly enhanced in the presence of hydrogen peroxide. We found that methylglyoxal in phosphate buffer was decomposed easily by hydrogen peroxide at room temperature to yield acetic acid and formic acid as major products and diacetyl as a minor product; acetyl radical was detected in the solution by ESR spectroscopy by the use of a spin-trapping reagent, 5,5-dimethyl-1-pyrroline N-oxide. Furthermore, guanosine was converted into N2-acetylguanosine by a combination of methylglyoxal and hydrogen peroxide in 0.1 M phosphate buffers (pH 6.1 to 7.4). This acetylation may be related to the enhancement of methylglyoxal mutagenicity by hydrogen peroxide. Other α-ketoaldehydes such as glyoxal and phenylglyoxal also yielded the corresponding acids and α-dicarbonyls upon reaction with hydrogen peroxide under the same conditions as above. These acids would have been produced through Baeyer-Villiger reaction or coupling of acyl radical with hydroxy radical, and dicarbonyls by dimerization of acyl radicals. In addition, when phenylglyoxal was used, the generation of benzoyl radical and the conversion of guanosine to N2-benzoylguanosine were observed. However, it remains to be established whether the generation of acyl radicals is directly involved in the N-2 acylation of guanosine.
- Nukaya,Inaoka,Ishida,Tsuji,Suwa,Wakabayashi,Kosuge
-
p. 649 - 653
(2007/10/02)
-
- A Regiocontrolled Synthesis of N7- and N9-Guanine Nucleosides
-
The reaction of 2-O-acetylated and 2-O-benzoylated glycosides 3a,b/4a,b with silylated N2-acetylguanine 7 selectively gave N7-guanine nucleosides 8a,b/9a,b under kinetically controlled conditions (SnCl4/CH3CN, room temperature), whereas 2-O-benzoylated glycosides 3b/4b selectively gave isomeric N9-guanine nucleosides 10b/11b under termodynamically controlled conditions (TMSOTf/(CH2Cl)2, reflux).Unambiguous assignment of nucleoside structure was accomplished after hydrolysis (NH3/MeOH) of the initial products to the known nucleosides 8c, 9c, 10c, and 11c followed by 1H NMR and 13C NMR spectral analysis.The described procedures provide the best method to date for the selective synthesis of either N7- or N9-guanine nucleosides from a common substrate.
- Garner, Philip,Ramakanth, Sarabu
-
p. 1294 - 1298
(2007/10/02)
-