Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidi... more Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidine ribonucleosides under potentially prebiotic conditions. Upon treatment with cyanoacetylene, 1 is transformed into alpha-D-cytidine (alpha-2), and if an efficient means of anomerising this nucleoside or a derivative thereof were to be found, then the synthesis of one of the key beta-D-nucleosides required to make RNA would be realised. Photoanomerisation of alpha-2 has previously been described, but the yield was extremely low. Therefore, the present study was initiated to determine whether this low yield was the result of a low conversion or competing reaction pathways.
New formamidine-3TC (3TC = 2',3'-dideoxy-3'-thiacytidine) analogues have been synthes... more New formamidine-3TC (3TC = 2',3'-dideoxy-3'-thiacytidine) analogues have been synthesized through various methods, and their antiviral activities (HIV, HBV) have been evaluated in vitro. Anti-HIV-1 in acutely infected MT-4 cells and peripheral blood monocellular cells (PBMCs) showed that compounds substituted by N,N-diarylformamidine side chains at the 4-N nucleic base position (compounds 3 and 8-11) had at least equivalent anti-HIV activity as 3TC (EC50 = 0.5 and 11.6 microM, respectively). Moreover, the newly synthesized compounds demonstrated higher anti-HBV activity (EC50 ranging from 0.01 to 0.05 microM) compared to the parent nucleoside 3TC (EC50 = 0.2 microM). It should be underlined that these new promising derivatives inhibited HIV in cells of a macrophage lineage, which are known to be cellular reservoir for HIV. These results were particularly of interest, since the antiviral activities appeared not to be mediated through the formamidine bond hydrolysis and co...
Skip to Main Content. Wiley Online Library will be disrupted 3 Dec from 10-12 GMT for monthly mai... more Skip to Main Content. Wiley Online Library will be disrupted 3 Dec from 10-12 GMT for monthly maintenance. ...
In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs whic... more In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome some drug deficiencies. Examples of antiviral carrier-linked nucleoside prodrugs or nucleoside bioprecursors are described, and their active mechanisms discussed. The described nucleoside prodrugs are classified in two structural classes: prodrugs bearing molecular modifications on the sugar moiety and prodrugs bearing molecular modifications on the nucleic base. Despite the important research work accomplished through out the world during the last few years in developing improved antiviral drugs for the treatment of HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HSV (herpes simplex virus), HCMV (human cytomegalovirus), etc infections, only few nucleoside antiviral prodrugs are marketed, while promising prodrugs deriving from original concepts were developed. The most relevant concepts are discussed: (1) - pronucleotide approach allows the design of prodrugs, which by-pass the first kinase phosphorylation step; (2) - drug design based on Bodor's concept for brain delivery improved drugs and (3) - 5'-O-carbonate nucleosides and deaminase approaches, which allow active drug regeneration. Nonetheless, none of these innovative models have reached the market.
For the RNA world hypothesis to be accepted, the constitutional self-assembly of RNA will have to... more For the RNA world hypothesis to be accepted, the constitutional self-assembly of RNA will have to be demonstrated. Conceptually, the simplest route to RNA involves nucleotide polymerisation. Activated pyrimidine nucleotides can be derived from arabinose-3-phosphate under potentially prebiotic conditions, but the prebiotic synthesis of this sugar phosphate has not hitherto been investigated. The results of synthetic approaches involving phosphorylation, phosphate migration and 2,3-C--C bond construction are described herein.
Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidi... more Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidine ribonucleosides under potentially prebiotic conditions. Upon treatment with cyanoacetylene, 1 is transformed into alpha-D-cytidine (alpha-2), and if an efficient means of anomerising this nucleoside or a derivative thereof were to be found, then the synthesis of one of the key beta-D-nucleosides required to make RNA would be realised. Photoanomerisation of alpha-2 has previously been described, but the yield was extremely low. Therefore, the present study was initiated to determine whether this low yield was the result of a low conversion or competing reaction pathways.
Spectacular advances in structural and molecular biology have added support to the 'RNA world' hy... more Spectacular advances in structural and molecular biology have added support to the 'RNA world' hypothesis, and provide a mandate for chemistry to explain how RNA might have been generated prebiotically on the early earth. Difficulties in achieving a prebiotically plausible synthesis of RNA, however, have led many to ponder the question posed in the title of this paper. Herein, we review recent experimental work on the assembly of potential RNA precursors, focusing on methods for stereoselective C-C bond construction by aldolisation and related processes. This chemistry is presented in the context of a broader picture of the potential constitutional self-assembly of RNA. Finally, the relative accessibility of RNA and alternative nucleic acids is considered.
Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidi... more Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidine ribonucleosides under potentially prebiotic conditions. Upon treatment with cyanoacetylene, 1 is transformed into alpha-D-cytidine (alpha-2), and if an efficient means of anomerising this nucleoside or a derivative thereof were to be found, then the synthesis of one of the key beta-D-nucleosides required to make RNA would be realised. Photoanomerisation of alpha-2 has previously been described, but the yield was extremely low. Therefore, the present study was initiated to determine whether this low yield was the result of a low conversion or competing reaction pathways.
New formamidine-3TC (3TC = 2',3'-dideoxy-3'-thiacytidine) analogues have been synthes... more New formamidine-3TC (3TC = 2',3'-dideoxy-3'-thiacytidine) analogues have been synthesized through various methods, and their antiviral activities (HIV, HBV) have been evaluated in vitro. Anti-HIV-1 in acutely infected MT-4 cells and peripheral blood monocellular cells (PBMCs) showed that compounds substituted by N,N-diarylformamidine side chains at the 4-N nucleic base position (compounds 3 and 8-11) had at least equivalent anti-HIV activity as 3TC (EC50 = 0.5 and 11.6 microM, respectively). Moreover, the newly synthesized compounds demonstrated higher anti-HBV activity (EC50 ranging from 0.01 to 0.05 microM) compared to the parent nucleoside 3TC (EC50 = 0.2 microM). It should be underlined that these new promising derivatives inhibited HIV in cells of a macrophage lineage, which are known to be cellular reservoir for HIV. These results were particularly of interest, since the antiviral activities appeared not to be mediated through the formamidine bond hydrolysis and co...
Skip to Main Content. Wiley Online Library will be disrupted 3 Dec from 10-12 GMT for monthly mai... more Skip to Main Content. Wiley Online Library will be disrupted 3 Dec from 10-12 GMT for monthly maintenance. ...
In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs whic... more In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome some drug deficiencies. Examples of antiviral carrier-linked nucleoside prodrugs or nucleoside bioprecursors are described, and their active mechanisms discussed. The described nucleoside prodrugs are classified in two structural classes: prodrugs bearing molecular modifications on the sugar moiety and prodrugs bearing molecular modifications on the nucleic base. Despite the important research work accomplished through out the world during the last few years in developing improved antiviral drugs for the treatment of HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HSV (herpes simplex virus), HCMV (human cytomegalovirus), etc infections, only few nucleoside antiviral prodrugs are marketed, while promising prodrugs deriving from original concepts were developed. The most relevant concepts are discussed: (1) - pronucleotide approach allows the design of prodrugs, which by-pass the first kinase phosphorylation step; (2) - drug design based on Bodor's concept for brain delivery improved drugs and (3) - 5'-O-carbonate nucleosides and deaminase approaches, which allow active drug regeneration. Nonetheless, none of these innovative models have reached the market.
For the RNA world hypothesis to be accepted, the constitutional self-assembly of RNA will have to... more For the RNA world hypothesis to be accepted, the constitutional self-assembly of RNA will have to be demonstrated. Conceptually, the simplest route to RNA involves nucleotide polymerisation. Activated pyrimidine nucleotides can be derived from arabinose-3-phosphate under potentially prebiotic conditions, but the prebiotic synthesis of this sugar phosphate has not hitherto been investigated. The results of synthetic approaches involving phosphorylation, phosphate migration and 2,3-C--C bond construction are described herein.
Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidi... more Recent work has emphasised the importance of D-ribose aminooxazoline 1 in the synthesis of cytidine ribonucleosides under potentially prebiotic conditions. Upon treatment with cyanoacetylene, 1 is transformed into alpha-D-cytidine (alpha-2), and if an efficient means of anomerising this nucleoside or a derivative thereof were to be found, then the synthesis of one of the key beta-D-nucleosides required to make RNA would be realised. Photoanomerisation of alpha-2 has previously been described, but the yield was extremely low. Therefore, the present study was initiated to determine whether this low yield was the result of a low conversion or competing reaction pathways.
Spectacular advances in structural and molecular biology have added support to the 'RNA world' hy... more Spectacular advances in structural and molecular biology have added support to the 'RNA world' hypothesis, and provide a mandate for chemistry to explain how RNA might have been generated prebiotically on the early earth. Difficulties in achieving a prebiotically plausible synthesis of RNA, however, have led many to ponder the question posed in the title of this paper. Herein, we review recent experimental work on the assembly of potential RNA precursors, focusing on methods for stereoselective C-C bond construction by aldolisation and related processes. This chemistry is presented in the context of a broader picture of the potential constitutional self-assembly of RNA. Finally, the relative accessibility of RNA and alternative nucleic acids is considered.
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