Bicyclic Nucleoside Analogues Research Articles

Specific recognition of the bicyclic pyrimidine nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded thymidine kinase.

Recently, an entirely new class of bicyclic nucleoside analogs (BCNAs) was found to display exquisite potency and selectivity as inhibitors of varicella-zoster virus (VZV) replication in cell culture. A striking difference in their ability to convert the BCNAs to their phosphorylated derivatives was observed between the VZV-encoded thymidine kinase (TK) and the very closely related herpes simplex virus type 1 (HSV-1) TK. Whereas VZV TK efficiently phosphorylated the BCNAs, HSV-1 TK was unable to do so. In addition, the thymidylate (dTMP) kinase activity of VZV TK further converted BCNA-5'-MP to BCNA-5'-DP. The BCNAs (or their phosphorylated derivatives) were not a substrate for cytosolic TK, mitochondrial TK, or cytosolic dTMP kinase. Human erythrocyte nucleoside diphosphate (NDP) kinase was unable to phosphorylate the BCNA 5'-diphosphates to BCNA 5'-triphosphates. Under the same experimental conditions, the anti-herpetic (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) derivative was efficiently converted to BVDU-MP and BVDU-DP by both VZV TK and HSV-1 TK and further, into BVDU-TP, by NDP kinase. Our observations may account for the unprecedented specificity of BCNAs as anti-VZV agents.

ChemInform Abstract: Novel Bicyclic Nucleoside Analogue (1S,5S,6S)‐6‐Hydroxy‐5‐hydroxymethyl‐1‐(uracil‐1‐yl)‐3,8‐dioxabicyclo [3.2.1]octane (I): Synthesis and Incorporation into Oligodeoxynucleotides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Novel bicyclic nucleoside analogue (1S,5S,6S)-6- hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane: synthesis and incorporation into oligodeoxynucleotides.

The novel bicyclic nucleoside (1S,5S,6S)-6-hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane [2'-deoxy-1'-C,4'-C-(2-oxapropano)uridine] (15), expected to be restricted into an O4'-endo furanose conformation, was synthesized from the known 1-(3'-deoxy-beta-D-psicofuranosyl)uracil 5. The phosphoramidite derivative of 15 was successfully incorporated into oligodeoxynucleotides using standard methods, and thermal denaturation studies showed moderate decreases in duplex stabilities of -2.1 and -1.5 degrees C per modification toward complementary DNA and RNA, respectively.

Bicyclic nucleoside inhibitors of Varicella-Zoster virus (VZV): the effect of terminal unsaturation in the side chain

Novel bicyclic nucleoside analogues bearing long alkyl side chains are prepared and tested as inhibitors of VZV. In particular, analogues with terminal unsaturation in the side chain are reported. Whilst terminal alkenyl derivatives are potent antivirals, the corresponding terminal alkynyls are poorly active.

ChemInform Abstract: Synthesis and Anti-HIV-1 Activity of Novel Bicyclic Nucleoside Analogues Restricted to an S-Type Conformation.

(1S,3R,4S)-3-Hydroxymethyl-1-(uracil-1-yl)-2,5-dioxabicyclo[2.2.1]heptane 9 and the corresponding cytosine derivative 10, nucleoside analogues with a novel bicyclic nucleoside structure 3, were synthesized in a few steps from the known 1-(3′-deoxy-β-D-psicofuranosyl)uracil 4. NOE experiments verified the bicyclic nucleosides to be restricted to the expected S-type furanose conformation while the nucleobase is in an anti-conformation. Both nucleosides proved to be devoid of anti-HIV activity in MT-4 cells, which further supports the hypothesis that conformational flexibility of the furanose ring in a nucleoside analogue is necessary to obtain both intracellular 5′-triphosphorylation and inhibition of HIV-1 reverse transcriptase.

Syntheses and properties of conformationally restrained nucleosides and oligonucleotides analogues

This review summarizes our efficient syntheses of novel bicyclic nucleoside analogues, 3'-O,4'-C-methyleneribonucleosides (1) (4-BC type nucleoside analogue), 2'-O,4'-C-methyleneribonucleosides (2) (5-BC), 3'-amino-3'-deoxy-3'-N,4'-C-methyleneribonucleosides (3) (aza 4-BC), and 3'-azido- and 3'-amino-3'-deoxy-2'-O,4'-C-methyleneribonucleosides (4, 5) (aza 5-BC). From 1H-NMR and X-ray crystallographic analyses, the 4-BC and aza 4-BC type nucleoside analogues (1, 3) were found to have a S-conformation predominantly, while the conformations of 5-BC and aza 5-BC type nucleoside analogues (2, 4, 5) were exclusively locked in N-form. The 4-BC and 5-BC type nucleoside analogues (1, 2) were effectively introduced into oligonucleotides using a DNA synthesizer. Furthermore, unprecedented hybridizing ability towards complementary RNA and DNA, RNA selectivity, potent triplex forming ability, and sufficient enzymatic stability of these modified oligonucleotides were also confirmed. These results should reveal a promising route to the development of antisense/antigene methodology.

Synthesis and anti-HIV-1 activity of novel bicyclic nucleoside analogues restricted to an S-type conformation

(1S,3R,4S)-3-Hydroxymethyl-1-(uracil-1-yl)-2,5-dioxabicyclo[2.2.1]heptane 9 and the corresponding cytosine derivative 10, nucleoside analogues with a novel bicyclic nucleoside structure 3, were synthesized in a few steps from the known 1-(3′-deoxy-β-D-psicofuranosyl)uracil 4. NOE experiments verified the bicyclic nucleosides to be restricted to the expected S-type furanose conformation while the nucleobase is in an anti-conformation. Both nucleosides proved to be devoid of anti-HIV activity in MT-4 cells, which further supports the hypothesis that conformational flexibility of the furanose ring in a nucleoside analogue is necessary to obtain both intracellular 5′-triphosphorylation and inhibition of HIV-1 reverse transcriptase.

Preparation and properties of 2′,5′-linked oligonucleotide analogues containing 3′- O,4′- C-methyleneribonucleosides

Bicyclic nucleoside analogues, 3′- O,4′- C-methyleneuridine and -5-methyluridine, were successfully incorporated into oligonucleotides via connection with 2′,5′-phosphodiester linkage, and hybridization behavior and nuclease stability of the modified oligonucleotides were investigated.

Facile synthesis and conformation of 3′-O,4′-C-methyleneribonucleosides

Bicyclic nucleoside analogues, 3′-O,4′-C-methyleneribonucleosides 1, including thymine, cytosine, adenine and guanine nucleobases, were conveniently synthesized from D-glucose, and the ribofuranose ring of 1 was found to exist predominantly in a S-conformation by means of 1H NMR and X-ray analysis.

Syntheses and Properties of Novel Conformationally Restrained Nucleoside Analogues.

This account describes our syntheses and conformational analyses of the bicyclic nucleoside analogues, 3'-O, 4'-C-methyleneribonucleosides (4-BC), 3'-amino-3'- deoxy-3'-O, 4'-C-methyleneribonucleosides (aza 4-BC), 2'-O, 4'-C-methyleneribonucleosides (5-BC), and 3'-amino- and 3'-azido-3'deoxy-2'-O, 4'-C-methyleneribonucleosides (aza 5-BC). The nucleoside analogues (4-BC and 5-BC) were effectively introduced into oligonucleotides by using a DNA synthesizer. Furthermore, unprecedented hybridizing ability towards complementary RNA and DNA, potent triplex-forming ability, and sufficient enzymatic stability of these modified oligonucleotides were also confirmed. From these studies, we believe that these conformationally restrained nucleoside analogues are good candidates for practical antisense/antigene molecules.

Stability and structural features of the duplexes containing nucleoside analogues with a fixed N-type conformation, 2′- O,4′- C-methyleneribonucleosides

Bicyclic nucleoside analogues with a fixed N-type conformation, 2′- O,4′- C-methyleneuridine and -cytidine, were incorporated into oligonucleotides, and the binding efficiency of the modified oligonucleotides to the complementary DNA and RNA as well as the CD spectra of the modified DNA-DNA and modified DNA-RNA duplexes were studied.

ChemInform Abstract: Synthesis and Conformation of 3′‐O,4′‐C‐Methyleneribonucleosides, Novel Bicyclic Nucleoside Analogues for 2′,5′‐Linked Oligonucleotide Modification.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of 2′- O,4′- C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C 3, -endo sugar puckering

2′- O,4′- C-Methyleneuridine and -cytidine, novel bicyclic nucleoside analogs having a typical C3′- endo sugar puckering, were synthesized starting from uridine via a several-step sequence.

Novel Bicyclic Nucleoside Analogues Related to Natural Griseolic Acids

Methodologies for the synthesis of novel isomeric nucleosides related to the natural, biologically-active griseolic acids are described. The carbohydrate precursor for the synthesis, 1,4:3,6-dianhydro-d-glucitol, can be prepared easily from d-glucitol.

Synthesis and conformation of 3′-O,4′-C-methyleneribonucleosides, novel bicyclic nucleoside analogues for 2′,5′-linked oligonucleotide modification

S. Obika, K. Morio, D. Nanbu and T. Imanishi, Chem. Commun., 1997, 1643 DOI: 10.1039/A704376G