Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs.
Phosphonomethoxy nucleoside analogs of the thymine containing nucleoside reverse transcriptase inhibitors (NRTIs), 3'-azido-2',3'-dideoxythymidine (AZT), 2',3'-didehydro-2',3'-dideoxythymidine (d4T), and 2',3'-dideoxythymidine (ddT), were synthesized. The anti-HIV activity against wild-type and several major nucleoside-resistant strains of HIV-1 was evaluated together with the inhibition of wild-type HIV reverse transcriptase (RT). Phosphonomethoxy analog of d4T, 8 (d4TP), demonstrated antiviral activity with an EC(50) value of 26 microM, whereas, phosphonomethoxy analogs of ddT, 7 (ddTP), and AZT, 6 (AZTP), were both inactive at concentrations up to 200 microM. Bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs improved the anti-HIV activity of 7 and 8 by >150-fold and 29-fold, respectively, allowing for antiviral resistance to be determined. The K65R RT mutant virus was more resistant to the bisPOC prodrugs of 7 and 8 than bisPOC PMPA (tenofovir DF) 1. However, bisPOC prodrug of 7 demonstrated superior resistance toward the RT virus containing multiple thymidine analog mutations (6TAMs) indicating that new phosphonate nucleoside analogs may be suitable for targeting clinically relevant nucleoside resistant HIV-1 strains.
Mackman
Richard L
RL
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. rmackman@gilead.com
Zhang
Lijun
L
Prasad
Vidya
V
Boojamra
Constantine G
CG
Douglas
Janet
J
Grant
Deborah
D
Hui
Hon
H
Kim
Choung U
CU
Laflamme
Genevieve
G
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 / Q000633:toxicity*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008697:Methane / Q000737:chemistry; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013936:Thymidine / Q000737:chemistry*
D019380:Anti-HIV Agents; D009705:Nucleosides; D009943:Organophosphorus Compounds; D011355:Prodrugs; D008697:Methane; D013936:Thymidine