title: Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs.
abstract: 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.
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. rmackman@gilead.com
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Vidya
authors.initials: V
authors.lastname: Prasad
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Boojamra
authors.forename: Janet
authors.initials: J
authors.lastname: Douglas
authors.forename: Deborah
authors.initials: D
authors.lastname: Grant
authors.forename: Hon
authors.initials: H
authors.lastname: Hui
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
authors.forename: Genevieve
authors.initials: G
authors.lastname: Laflamme
authors.forename: Jay
authors.initials: J
authors.lastname: Parrish
authors.forename: Antitsa D
authors.initials: AD
authors.lastname: Stoycheva
authors.forename: Swami
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Keyu
authors.initials: K
authors.lastname: Wang
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
mesh_terms: 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*
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D009943:Organophosphorus Compounds; D011355:Prodrugs; D008697:Methane; D013936:Thymidine