Structure-activity relationships for phosphorylation of nucleoside analogs to monophosphates by nucleoside kinases.

The mammalian deoxyribonucleoside kinases thymidine kinase 1 and 2, deoxycytidine kinase and deoxyguanosine kinase phosphorylate deoxyribonucleosides and provide an alternative to de novo synthesis of DNA precursors. Their activities are essential for activation of several chemotherapeutically important nucleoside analogs. These four salvage kinase enzymes exhibit distinct substrate specificities for nucleoside analogs modified in the base and glycon moieties. In this review their. structure-activity relationships are discussed. Alternative routes for phosphorylation of nucleoside analogs are also reviewed, such as the phosphotransfer capacity of 5'-nucleotidase and protein kinases.

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Faculty Opinions recommendation of A short de novo synthesis of nucleoside analogs.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738455036.793577449 ◽

2020 ◽

Author(s):

Michal Hocek

Keyword(s):

De Novo ◽

Nucleoside Analogs ◽

De Novo Synthesis

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Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.33.12.2083 ◽

1989 ◽

Vol 33 (12) ◽

pp. 2083-2088 ◽

Cited By ~ 42

Author(s):

R Koshida ◽

S Cox ◽

J Harmenberg ◽

G Gilljam ◽

B Wahren

Keyword(s):

Human Immunodeficiency Virus ◽

Synergistic Effect ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Nucleoside Analogs ◽

Structure Activity Relationships ◽

Structure Activity ◽

Immunodeficiency Virus

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Metabolism in Human Cells of the d and l Enantiomers of the Carbocyclic Analog of 2′-Deoxyguanosine: Substrate Activity with Deoxycytidine Kinase, Mitochondrial Deoxyguanosine Kinase, and 5′-Nucleotidase

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.5.1045 ◽

1998 ◽

Vol 42 (5) ◽

pp. 1045-1051 ◽

Cited By ~ 8

Author(s):

L. Lee Bennett ◽

Paula W. Allan ◽

Gussie Arnett ◽

Y. Fulmer Shealy ◽

Donna S. Shewach ◽

...

Keyword(s):

Biological Activity ◽

Nucleoside Analogs ◽

Human Platelets ◽

Biologically Active ◽

Deoxycytidine Kinase ◽

Link Type ◽

Duck Hepatitis ◽

B Virus ◽

Deoxyguanosine Kinase ◽

Infected Cells

ABSTRACT The carbocyclic analog of 2′-deoxyguanosine (CdG) has broad-spectrum antiviral activity. Because of recent observations with other nucleoside analogs that biological activity may be associated thel enantiomer rather than, as expected, with thed enantiomer, we have studied the metabolism of both enantiomers of CdG to identify the enzymes responsible for the phosphorylation of CdG in noninfected and virally infected human and duck cells. We have examined the enantiomers as substrates for each of the cellular enzymes known to catalyze phosphorylation of deoxyguanosine. Both enantiomers of CdG were substrates for deoxycytidine kinase (EC 2.7.1.74) from MOLT-4 cells, 5′-nucleotidase (EC 3.1.3.5) from HEp-2 cells, and mitochondrial deoxyguanosine kinase (EC 2.7.1.113) from human platelets and CEM cells. For both deoxycytidine kinase and mitochondrial deoxyguanosine kinase, thel enantiomer was the better substrate. Even though thed enantiomer was the preferred substrate with 5′-nucleotidase, the rate of phosphorylation of the lenantiomer was substantial. The phosphorylation of d-CdG in MRC-5 cells was greatly stimulated by infection with human cytomegalovirus. The fact that the phosphorylation of d-CdG was stimulated by mycophenolic acid and was not affected by deoxycytidine suggested that 5′-nucleotidase was the enzyme primarily responsible for its metabolism in virally infected cells.d-CdG was extensively phosphorylated in duck hepatocytes, and its phosphorylation was not affected by infection with duck hepatitis B virus. These results are of importance in understanding the mode of action of d-CdG and related analogs and in the design of new biologically active analogs.

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The power of ribosome display for de novo ligand design: identification, structure-activity relationships, and application of a novel streptavidin affinity peptide

10.1240/sav_gbm_2005_h_001392 ◽

2005 ◽

Vol 2005 (Fall) ◽

Author(s):

Arnd B. E. Brauer ◽

Thorsten Lamla ◽

Charlotte Förster ◽

Svenja Brode ◽

Sandro Keller ◽

...

Keyword(s):

De Novo ◽

Ligand Design ◽

Ribosome Display ◽

Structure Activity Relationships ◽

Structure Activity ◽

Affinity Peptide

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A short de novo synthesis of nucleoside analogs

Science ◽

10.1126/science.abb3231 ◽

2020 ◽

Vol 369 (6504) ◽

pp. 725-730 ◽

Cited By ~ 4

Author(s):

Michael Meanwell ◽

Steven M. Silverman ◽

Johannes Lehmann ◽

Bharanishashank Adluri ◽

Yang Wang ◽

...

Keyword(s):

Drug Discovery ◽

Viral Infections ◽

De Novo ◽

Nucleoside Analogs ◽

Aldol Reactions ◽

Displacement Reaction ◽

De Novo Synthesis ◽

One Pot ◽

Drug Discovery And Development ◽

Locked Nucleic Acids

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.

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