BLD Insights
Discussion on Modified Nucleosides
15 March 2022
5-(Hydroxymethyl)-1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione
3',5'-O-(1,1,3,3-TEtraisopropyl-1,3-disiloxanediyl)guanosine
1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-methylpyrimidine-2,4(1H,3H)-dione
1-((2R,3R,4R,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxytetrahydrofuran-2-yl)-4-(1H-1,2,4-triazol-1-yl)pyrimidin-2(1H)-one
1-((2R,3R,4R,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl diacetate
1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one
(2R,3R,4S,5R)-2-(6-(Dimethylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol
N4-Methylcytidine
Nucleosides are important raw materials for DNA and RNA in organisms and play a key role in various cellular processes ranging from cell signaling to cell proliferation. There are 8 kinds of natural nucleosides (Fig.1) and other modified nucleosides in cells (Fig.2). 1 Related research on modified nucleosides is advancing to explore the function and mechanism of modified nucleosides in organisms. And the study achievements are widely used in medicinal chemistry chemical biology. 2-5
Fig.1: The most common nucleosides in RNA and DNA 6
Fig.2: Naturally modified nucleosides in organisms
Mechanism
Modified nucleosides are phosphorylated in cells and will be recognized by host cells or viral enzymes to play a bioactive role: (1) They will compete with normal nucleosides and inhibit the growth of cancer cells, the replication of virus and other disease processes. (2) Triphosphate modified nucleotides can replace natural nucleotides and adjust the fate or function of DNA or RNA by changing base pairing, Π-Π stacking, or metal chelation. 7, 8 Due to the importance of DNA and RNA replication in rapidly proliferating tumor cells and virus replication, modified nucleosides can be used as drug molecules to treat diseases such as cancer and viral infections (Fig.3). 7, 9
Fig.3: The mechanism of modified nucleosides in the cell. Cellular uptake of nucleoside analogues is an active process involving concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). Modified nucleoside undergoes an initial rate-limiting phosphorylation step by a nucleoside kinase, which leads to the production of a monophosphate metabolite. A second phosphorylation step is then performed by nucleoside monophosphate kinase, and the third phosphorylation step is performed by nucleoside diphosphate kinase. Triphosphates can be incorporated in nucleic acids, in competition with their normal counterparts.
Optimization Strategy
Modified nucleosides are mainly used in the research and development of the following types of drugs (1) Anticancer drugs: cytarabine, azacitidine, gemcitabine, etc.(2) rheumatism drugs: azathioprine, allopurinol, etc.(3) antiviral drugs: acyclovir, monupivir, etc.(4) Antibiotics: trimethoprim, capillin, polyoxin J, etc.(5) Raw materials for nucleic acid drugs (such as DNA/RNA vaccines).4, 6, 10-17
In the research and development of related drugs, modification of nucleoside bases, glycosidic bonds and sugar rings is a common strategy to improve the pharmacokinetic and pharmacodynamic properties, reduce the immunogenicity of nucleic acid drugs and improve the stability: (1) Modification of sugar ring: PSI-6206 introduce substituents on the C2-5 position of furanose. It can improve metabolic stability and affect the conformation of furanose. The hydroxyl group of Molnupiravir is blocked with an acyl group to make a prodrug, which can effectively improve its cell membrane permeability. (2) Unnatural base modification: Modification of nucleosides based can also obtain better bioactivity and drug-like properties (such as Ribavirin). 18 (3) Change the connection mode of glycosidic bonds: such as changing the C-N bond to C-C/C-O/C-S and other connection methods can improve its metabolic properties (Fig.4).
Fig.4: Approved drugs or preclinical drug candidates depended on modified nucleosides
Other Applications
Modified nucleosides are widely used in other aspects, such as the diagnosis of disease. With reporter groups (such as isotopic labels or fluorophores) or functional groups (such as azide, alkynyl, etc.), we could achieve the real-time localization or quantitative detection of nucleic acids. And it can be used to explore the structure, function, and fate of nucleic acids under physiological conditions (FIG.5, 6). (such as nucleic acid-protein interactions, nucleic acid structure, kinetic characteristics, etc.) 3, 19-22
Fig.5: Imagining of [18F]-Fludarabine in a xenograft model
Fig.6: Synthesis route of [18F]-Fludarabine
References
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