- Di-ddU-α-hydroxyphosphonate and α-hydroxy-α-methylphosphonates as potential prodrugs of antiviral nucleoside analogues
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The synthesis of a potential new prodrug system for the antiviral nucleoside ddU 1 based on α-hydroxybenzylphosphonates 2 and 3 is described. In principle, 2, 3 are able to hydrolyze via different mechanisms yielding ddU H-phosphonate 4 or ddU monophosphate 5, respectively.
- Habel, Lothar W.,Meier, Chris
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- Nucleoside mono- and diphosphate prodrugs of 2′,3′-dideoxyuridine and 2′,3′-dideoxy-2′,3′-didehydrouridine
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Despite their close structural similarity to nucleoside analogues such as the anti-HIV drugs AZT and d4T, 2′,3′-dideoxyuridine (ddU) and 2′,3′-dideoxy-2′,3′-didehydrouridine (d4U) are entirely inactive against HIV in their nucleoside form. However, it has been shown that the corresponding triphosphates of these two nucleosides can effectively block HIV reverse transcriptase. Herein we report on two types of nucleotide prodrugs (cyclo-Sal and DiPPro nucleotides) of ddU and d4U to investigate their ability to overcome insufficient intracellular phosphorylation, which may be the reason behind their low anti-HIV activity. The release of the corresponding mono- and diphosphates from these compounds was demonstrated by hydrolysis studies in phosphate buffer (pH 7.3) and human CD4+ T-lymphocyte CEM cell extracts. Surprisingly, however, these compounds showed low or no anti-HIV activity in tests with human CD4+ T-lymphocyte CEM cells. Studies of the conversion of ddUDP and d4UDP into their triphosphate metabolites by nucleoside diphosphate kinase (NDPK) showed nearly no conversion of either diphosphate, which may be the reason for low intracellular triphosphate levels that result in low antiviral activity.
- Pertenbreiter, Florian,Balzarini, Jan,Meier, Chris
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- Developing a collection of immobilized nucleoside phosphorylases for the preparation of nucleoside analogues: Enzymatic synthesis of arabinosyladenine and 2',3'-dideoxyinosine
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The use of nucleoside phosphorylases (NPs; EC 2.4.2.n) represents a convenient alternative to the chemical route for the synthesis of natural and modified nucleosides. We purified four recombinantly expressed nucleoside phosphorylases from the bacterial pathogens Citrobacter koseri, Clostridium perfringens, and Streptococcus pyogenes (CkPNPI, CkPNPII, CpUP, SpUP) and their substrate specificity was investigated towards either natural pyrimidine or purine nucleosides and some analogues, namely, arabinosyladenine (araA) and 2',3'-dideoxyinosine (ddI). A 2-3 % activity towards these latter compounds (compared to the natural substrates) was observed. Enzyme activities were compared to the specificities obtained for the enzymes pyrimidine nucleoside phosphorylase from Bacillus subtilis (BsPyNP) and purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNPII) previously reported by some of the authors. The enzymes displaying the suitable specificity for the synthesis of araA and ddI were immobilized on aldehyde-agarose. The immobilized preparations were highly stable at alkaline pH and in the presence of methanol or acetonitrile as cosolvent. They were used in the synthesis of araA and ddI by a one-pot, bienzymatic transglycosylation achieving 74 and 44 % conversion, respectively. Something different: Nucleoside phosphorylases are a convenient alternative to the chemical route for the synthesis of natural and modified nucleosides. Four new nucleoside phosphorylases have been prepared, characterized, and tested for their use in biocatalyzed syntheses of araA and ddI (see scheme). A generally applicable immobilization technique has been found to provide active and stable biocatalysts.
- Serra, Immacolata,Ubiali, Daniela,Piskur, Jure,Christoffersen, Stig,Lewkowicz, Elizabeth S.,Iribarren, Adolfo M.,Albertini, Alessandra M.,Terreni, Marco
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p. 157 - 165
(2013/04/24)
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- An investigation into the anti-HIV activity of 2′,3′-didehydro- 2′,3′-dideoxyuridine (d4U) and 2′,3′-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives
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As part of our studies on the anti-HIV activities of 2′,3′- didehydro-2′,3′-dideoxyuridine (d4U), 2′,3′- dideoxyuridine (ddU) and their 'ProTides', we have prepared and evaluated the anti-HIV activity of a range of d4U and ddU aryl triester phosphoramidates. Besides elucidating SAR characteristics, we performed molecular modelling studies on both d4U and ddU in order to probe the first phosphorylation step required for the activation of these two nucleoside analogues. Overall, the application of the phosphoramidate approach turned the inactive ddU to a moderately active anti-HIV agent, while this was not the case with d4U. Enzymatic assays investigating the metabolism of d4U phosphoramidates revealed an efficient cleavage of the phosphoramidate motif to release the d4U monophosphate. Thus, a poor second and/or third phosphorylation step may be the most likely reason for the virtual lack of anti-HIV activity in this case. The Royal Society of Chemistry 2009.
- Mehellou, Youcef,Balzarini, Jan,McGuigan, Christopher
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supporting information; experimental part
p. 2548 - 2553
(2009/10/30)
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- FLUORESCENT NUCLEOSIDE ANALOGUES
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Briefly described, embodiments of the present disclosure include novel fluorescent nucleoside analogs (fNAs) including a fluorescent nucleobase, selected from a purine and a pyrimidine base or analog thereof, and a modified sugar moiety that differs in structure from a sugar moiety of a naturally occurring nucleoside. In embodiments, the fNAs of the present disclosure are analogues of NA prodrugs used to treat viral disorders. Embodiments of the present disclosure also include methods of making the novel fNAs of the present disclosure.
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Page/Page column 27
(2008/12/07)
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- Design, synthesis, and anti-HIV activity of 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U), 2′,3′-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives
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We report the synthesis of 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U) and 2′,3′-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.
- Mehellou, Youcef,McGuigan, Christopher,Brancale, Andrea,Balzarini, Jan
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p. 3666 - 3669
(2008/02/05)
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- Synthesis of conjugates of 2′,3′-dideoxynucleoside-5′- monophosphates with α-amino acids
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Previously undescribed conjugates of 2′,3′-dideoxyuridine- 5′-monophosphate-(L)-methoxytryptophylphosphoramidate (5) and 2′,3′-dideoxycytidine-5′-monophosphate-(L)- methoxytryptophylphosphoramidate (7) were isolated by a chemical enzymatic method in order to study their pharmacological properties and to prepare new medicinal preparations based on them. 2006 Springer Science+Business Media, Inc.
- Zhernosek,Kvach,Eroshevskaya,Kalinichenko,Zinchenko
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p. 208 - 211
(2008/02/01)
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- Discovery of a New Family of Inhibitors of Human Cytomegalovirus (HCMV) Based upon Lipophilic Alkyl Furano Pyrimidine Dideoxy Nucleosides: Action via a Novel Non-Nucleosidic Mechanism
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Following our discovery of the potent anti-varicella zoster virus action of lipophilic alkyl furano pyrimidine 2′-deoxynucleosides, we now report that 2′,3′-dideoxy sugar analogues are devoid of anti-VZV activity but are potent and selective inhibitors of human cytomegalovirus (HCMV). The present compounds are active in vitro at ca. 1 μM with cytotoxicity only above 200 μM. Importantly, we have discovered that the new agents do not act as nucleoside analogues, despite their nucleosidic structure, and time of addition studies revealed that the compounds may inhibit HCMV at an event in the replication cycle of the virus that precedes DNA synthesis. They represent new leads in the discovery of improved therapies for HCMV, particularly in view of their novel mechanism of action.
- McGuigan, Christopher,Pathirana, Ranjith N.,Snoeck, Robert,Andrei, Graciela,De Clercq, Erik,Balzarini, Jan
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p. 1847 - 1851
(2007/10/03)
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- Expeditious syntheses of sugar-modified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophene-based siloxy dienes
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A series of individual sugar-modified pyrimidine nucleosides including enantiomerically enriched 2',3'-dideoxynucleosides 14a-c (α and β anomers of L- and D-series), 2',3'-dideoxy-4'-thionucleosides 21a-c (α and β anomers of L- and D-series), and 2',3'-dideoxy-4'-azanucleosides 28a-c (β anomers of L- and D-series) were synthesized, with uniform chemistry and high stereochemical efficiency, exploiting a triad of versatile heterocyclic siloxy dienes, namely, 2-(tert-butyldimethylsiloxy)furan (TBSOF), 2-(tert- butyldimethylsiloxy)thiophene (TBSOT), and N-(tert-butoxycarbonyl)-2-(tert- butyldimethylsiloxy)pyrrole (TBSOP). The synthetic procedure advantageously used both enantiomers of glyceraldehyde acetonide (D-1 and L-1) as sources of chirality and as synthetic equivalents of the formyl cation. The outlined chemistry also allowed for the rapid assemblage of a 30-member collection of racemic nucleosides (D,L-L) as well as one 15-member ensemble of chiral analogues (L-L), along with some related sublibraries.
- Rassu, Gloria,Zanardi, Franca,Battistini, Lucia,Gaetani, Enrico,Casiraghi, Giovanni
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p. 168 - 180
(2007/10/03)
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- Antiviral agents
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Nucleoside compounds of the formula STR1 wherein: B is a purine or a pyrimidine; X and X' are H, OH or F, provided that at least one is H; Y and Y' are H, OH, OCH3 or F, provided that at least one is H; Y' and Z together form a cyclic phosphate ester, provided that Y is H; or Z is STR2 where n is zero, one, two or three; and Z' is N3 or OCH3 ; provided that when X' and Y' are OH and Z' is N3, B is not cytosine, and when X' and Y' are OH and Z' is OCH3, B is not uracil, adenine or cytosine; and the pharmaceutically acceptable esters, ethers and salts thereof, have been found to have potent antiviral activity with a high therapeutic ratio.
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- Stereocontrolled synthesis of pyrimidine 2',3'-dideoxy-β-nucleosides by intramolecular glycosylation
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β-2',3'-Dideoxynucleosides and their 3'-azido and 3'-fluoro substituted derivatives were synthesized in a stereocontrolled manner by the dimethyl(methylthio)sulfonium tetrafluoroborate promoted intramolecular glycosylation of phenyl 2,3-dideoxy-5-O-(2-pyrimidyl)-1-thioglycosides followed by hydrolysis or ammonolysis.
- Sujino,Sugimura
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p. 1883 - 1886
(2007/10/02)
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- 4'-substituted nucleosides
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Nucleosides compounds of Formula I: STR1 wherein B is a purine or a pyrimidine; X and X' are H; Y is H; Y' is OH, F or H; or Y' and X' together makes a bond; Z is STR2 where n is zero, one, two or three; or Y' and Z together form a cyclic phosphate ester; Z' is --CN, --CH3, CH2 N3 or --CH2 J, where J is a halogen atom; or Z' and Y' together are --CH2 O--; and pharmaceutically acceptable esters, ethers, amides, N-acyl moieties and salts thereof.
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- Efficient Synthesis of 2',3'-Dideoxynucleosides and 2',3'-Dideoxy C-Nucleosides from D-Glucosamine
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D-Glucosamine 1 can be easily converted into 2,5-anhydro-6-O-benzoyl-3,4-dideoxygluconic acid 6 which can be taken on to both 2',3'-dideoxynucleosides such as dideoxyuridine (ddU) 4 and 2',3'-dideoxy C-nucleosides such as dideoxyformycin B 5 and dideoxyshowdomycin 20.
- Jung, Michael E.,Trifunovich, Ivan D.
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p. 2921 - 2924
(2007/10/02)
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- A Highly Stereoselective Synthesis of Anti-HIV 2',3'-Dideoxy- and 2',3'-Didehydro-2',3'-dideoxynucleosides
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A general total synthesic method for the stereocontrolled synthesis of 2',3'-dideoxy- as well as 2',3'-didehydro-2',3'-dideoxynucleosides is presented.Introduction of an α-phenylselenenyl group at the 2-position of 2,3-dideoxyribosyl acetate directs the glycosyl bond formation to give >/=95percent β-isomer.This 2'-phenylselenenyl nucleoside may be converted to either the 2',3'-dideoxynucleoside by treatment with n-Bu3SnH and Et3B at room temperature or to the unsaturated derivative by treatment with H2O2/cat. pyridine.The application of this method to the syntheses of pyrimidines (ddU, ddT, ddC), 6-substituted purines (ddA, ddI, 6-chloro-ddP, N6-Me-ddA), and 2,6-disubstituted purines (2-F-ddA, 6-chloro-2-amino-ddP) as well as selected 2',3'-didehydro-2',3'-dideoxy derivatives is reported.
- Beach, J. Warren,Kim, Hea O.,Jeong, Lak S.,Nampalli, Satyanarayana,Islam, Qamrul,et al.
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p. 3887 - 3894
(2007/10/02)
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- Production of 2',3'-dideoxy-2',3'-didehydronucleosides
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There are disclosed novel processes for producing 2',3'-dideoxy-2'3'-didehydronucleosides, for example, 2',3'-dideoxy-2',3'-didehydrothymidine in high yields and on a large scale. The compounds so-produced are useful as antiviral agents, especially as agents effective against the human immunodeficiency viruses (HIV).
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- Process for purifying 2',3'-dideoxynucleosides
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A biological process for producing a 2',3'-dideoxynucleoside from 2',3'-dideoxyuridine is disclosed. the 2',3'-dideoxynucleoside can be purified readily using a porous nonpolar resin adsorbent.
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- Analogs of pyrimidine nucleosides. 16. Racemic 2′,3′-dideoxynucleosides and their derivatives
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The chlorination of 2-halomethyltetrahydrofurans and acyl derivatives of tetrahydrofuryl alcohol wasstudied; mixtures of 2,5- and 2,2-disubstituted tetrahydrofurans are formed as a result of the reaction. 2,4-Bis(trimethylsilyl) derivatives of uracil, 5-substituted uracils, and cytosine are alkylated by the resulting mixtures of α-chloro ethers without separation, and mixtures of cis and transisomers of 1-(5-substituted-2-tetrahydrofuryl) and 1-(2-substituted-2-tetrahydrofuryl) derivatives of uracil, 5-substituted uracils, and cytosine are obtained. The reaction products were identified onthe basis of their PMR spectra.
- Kaulinya,Liepin'sh,Lidak,Zhuk
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