Synthesis And Anti-Hiv Activity Of Cyclic Pyrimidine Phosphonomethoxy Nucleosides And Their Prodrugs: A Comparison Of Phosphonates And Corresponding Nucleosides

Cyclic phosphonomethoxy pyrimidine nucleosides that are bioisosteres of the monophosphate metabolites of HIV reverse transcriptase (RT) inhibitors AZT, d4T, and ddC have been synthesized. The RT inhibitory activities of the phosphonates were reduced for both dideoxy (dd) and dideoxydidehydro (d4) an...

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Published in:Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2007-01, Vol.26 (6-7), p.573-577
Main Authors: Mackman, Richard L., Zhang, Lijun, Prasad, Vidya, Boojamra, Constantine G., Chen, James, Douglas, Janet, Grant, Deborah, Laflamme, Genevieve, Hui, Hon, Kim, Choung U., Parrish, Jay, Stoycheva, Antitsa D., Swaminathan, Swami, Wang, KeYu, Cihlar, Tomas
Format: Article
Language:English
Subjects:
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - chemistry
antiviral
Cyclization - drug effects
Drug Resistance, Viral - drug effects
HIV
Nucleosides - chemical synthesis
Nucleosides - chemistry
Organophosphonates - chemical synthesis
Organophosphonates - chemistry
Phosphonate
prodrugs
Prodrugs - chemical synthesis
Prodrugs - chemistry
Reverse Transcriptase Inhibitors - chemistry
Reverse Transcriptase Inhibitors - pharmacology
Zidovudine - chemistry
Zidovudine - pharmacology
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Summary:Cyclic phosphonomethoxy pyrimidine nucleosides that are bioisosteres of the monophosphate metabolites of HIV reverse transcriptase (RT) inhibitors AZT, d4T, and ddC have been synthesized. The RT inhibitory activities of the phosphonates were reduced for both dideoxy (dd) and dideoxydidehydro (d4) analogs compared to the nucleosides. Bis-isopropyloxymethylcarbonyl (BisPOC) prodrugs were prepared on selected compounds and provided > 150-fold improvements in antiviral activity.
ISSN:1525-7770
1532-2335
DOI:10.1080/15257770701490126