Bis(tBuSATE) phosphotriester prodrugs of 8-azaguanosine and 6-methylpurine riboside; bis(pom) phosphotriester prodrugs of 2'-deoxy-4'-thioadenosine and its corresponding 9alpha anomer.
As an extension of previous work with bis(POM) nucleotide prodrugs, we report the synthesis and biological evaluation in tumor cell culture of the bis(pivaloyloxymethyl) phosphotriester prodrug of slightly cytotoxic 2'-deoxy-4'-thioadenosine and its alpha-anomer. We have experienced need for an alternative phosphate masking group, particularly with purine nucleosides. Accordingly, we report synthesis and biological evaluation of the bis(tBuSA TE) phosphotriester prodrugs of 8-azaguanosine and 6-methylpurine riboside, nucleoside analogs with moderate to significant cytotoxicity. All four prodrugs were examined in tumor cell culture in parallel with the parent nucleosides. Synthetic routes and biological data are presented.
Rose
J D
JD
Southern Research Institute, Birmingham, Alabama, USA.
Parker
W B
WB
Secrist
J A
JA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002845:Chromatography; D002855:Chromatography, Thin Layer; D054306:Dideoxynucleotides; D015195:Drug Design; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009705:Nucleosides / Q000737:chemistry; D063065:Organophosphonates / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013872:Thionucleosides / Q000737:chemistry*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D054306:Dideoxynucleotides; D009705:Nucleosides; D063065:Organophosphonates; D010710:Phosphates; D011355:Prodrugs; D013872:Thionucleosides; C504684:hydroxy tBuSATE phenylphosphotriester AZT derivative; D006151:Guanosine; C013405:azaguanosine; C050070:4'-thioadenosine; D015215:Zidovudine; D000241:Adenosine