Enhancement of Nucleoside Cytotoxicity through Nucleotide Prodrugs

• Published in: Journal of medicinal chemistry Vol. 45; no. 20; pp. 4505 - 4512
• Main Authors: Rose, Jerry D, Parker, William B, Someya, Hitoshi, Shaddix, Sue C, Montgomery, John A, Secrist, John A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.09.2002; Amer Chemical Soc
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - chemical synthesis; Adenosine Monophosphate - chemistry; Adenosine Monophosphate - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Deoxyadenosines - analogs & derivatives; Deoxyadenosines - chemical synthesis; Deoxyadenosines - chemistry; Deoxyadenosines - pharmacology; DNA - antagonists & inhibitors; DNA - biosynthesis; DNA Polymerase I - chemistry; Drug Screening Assays, Antitumor; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Nucleoside analogs; nucleoside kinase; Nucleosides; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; RNA - antagonists & inhibitors; RNA - biosynthesis; Science & Technology; Tumor Cells, Cultured; Uridine Kinase - metabolism; RIBONUCLEOTIDE REDUCTASE; CELLS; 2-CHLORO-9-(2-DEOXY-2-FLUORO-BETA-D-ARABINOFURANOSYL)ADENINE; DNA-POLYMERASES; 5'-MONOPHOSPHATE; DELIVERY; Antineoplastic agent; Purine nucleotide; Cytotoxicity; DNA synthesis; Prodrug; Deoxyribonucleotide; Metabolism; In vitro; Biological activity; Ester; Azanucleotide; Cell line; Inhibition; Mechanism of action; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020107s

A common reason for the lack of cytotoxicity of certain nucleosides is thought to be their inability to be initially activated to the monophosphate level by a nucleoside kinase or other activating enzyme. In a search for other nucleosides that might be worthwhile anticancer agents, we have begun to examine the utilization of monophosphate prodrugs in order to explore whether any enhanced cytotoxicity might be found for the prodrugs of candidate nucleosides that have little or no cytotoxicity. To that end, 5‘-bis(pivaloyloxymethyl) phosphate prodrugs of two weakly cytotoxic compounds, 8-aza-2‘-deoxyadenosine (5) and 8-bromo-2‘-deoxyadenosine (9), have been prepared. These prodrugs (8 and 12) were examined for their cytotoxicity in CEM cells and were found to possess significantly enhanced cytotoxicity when compared with the corresponding parent nucleosides. Further cell culture experiments were conducted to gain insight into the mechanisms of cytotoxicity of these two prodrugs, and those data are reported.