5'-Phosphoramidates and 5'-diphosphates of 2'-O-allyl-beta-D-arabinofuranosyluracil, -cytosine, and -adenine: inhibition of ribonucleotide reductase
| Autor: | Silvia Vertuani, Pier Giovanni Baraldi, Stefano Manfredini, Lars Thelander, Elisa Durini, Jan Balzarini, Erik De Clercq, Valentina Buzzoni,†,⊥ and, Anna Karlsson |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Stereochemistry Antineoplastic Agents Reductase Thymidine Kinase chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Deoxycytidine Kinase Ribonucleotide Reductases Tumor Cells Cultured Animals Humans Prodrugs Phosphorylation chemistry.chemical_classification biology Kinase organic chemicals Arabinofuranosyluracil Cytarabine food and beverages Prodrug Recombinant Proteins Ribonucleotide reductase Enzyme Biochemistry chemistry Enzyme inhibitor Thymidine kinase biology.protein Molecular Medicine Drug Screening Assays Antitumor Cytosine Vidarabine |
| Zdroj: | Journal of medicinal chemistry. 42(17) |
| ISSN: | 0022-2623 |
| Popis: | Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now prepared the diphosphates (DP) of 2'-O-allyl-1-beta-D-arabinofuranosyl-uracil and -cytosine and 2'-O-allyl-9-beta-D-arabinofuranosyl-adenine and evaluated their inhibitory activity against recombinant murine RNR. 2'-O-Allyl-araUDP proved to be inhibitory to RNR at an IC(50) of 100 microM, whereas 2'-O-allyl-araCDP was only marginally active (IC(50) 1 mM) and 2'-O-allyl-araADP was completely inactive. The susceptibility of the parent nucleosides to phosphorylation by thymidine kinase and 2'-deoxycytidine kinase was also investigated, and all nucleosides proved to be poor substrates for the above-cited kinases. Moreover, prodrugs of 2'-O-allyl-araU and -araC monophosphates, namely 2'-O-allyl-5'-(phenylethoxy-L-alanyl phosphate)-araU and -araC, were prepared and tested against tumor cell proliferation but proved to be inactive. A molecular modeling study has been conducted in order to explain our results. The data confirm that for both the natural and analogue nucleoside diphosphates, the principal determinant interaction with the active site of RNR is with the diphosphate group, which forms strong hydrogen bonds with Glu623, Thr624, Ser625, and Thr209. Our findings indicate that the poor phosphorylation may represent an explanation for the lack of marked in vitro cytostatic activity of the test compounds. |
| Databáze: | OpenAIRE |
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