Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs

  • Bioorg Med Chem. 2007 Aug 15;15(16):5519-28. doi: 10.1016/j.bmc.2007.05.047.
Richard L Mackman  1 ,  Lijun Zhang ,  Vidya Prasad ,  Constantine G Boojamra ,  Janet Douglas ,  Deborah Grant ,  Hon Hui ,  Choung U Kim ,  Genevieve Laflamme ,  Jay Parrish ,  Antitsa D Stoycheva ,  Swami Swaminathan ,  Keyu Wang ,  Tomas Cihlar
Affiliations
  • 1. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. [email protected]
PMID: 17562366 DOI: 10.1016/j.bmc.2007.05.047
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.