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) analogs compared to the nucleosides. Bis-isopropyloxymethylcarbonyl (BisPOC) prodrugs were prepared on selected compounds and provided > 150-fold improvements in antiviral activity.
Mackman
Richard L
RL
Gilead Sciences, Inc., Foster City, California 94404, USA. rmackman@gilead.com
Zhang
Lijun
L
Prasad
Vidya
V
Boojamra
Constantine G
CG
Chen
James
J
Douglas
Janet
J
Grant
Deborah
D
Laflamme
Genevieve
G
Hui
Hon
H
Kim
Choung U
CU
Parrish
Jay
J
Stoycheva
Antitsa D
AD
Swaminathan
Swami
S
Wang
KeYu
K
Cihlar
Tomas
T
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000187:drug effects; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015215:Zidovudine / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine