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

• Published in: Bioorganic & medicinal chemistry 2007-08, Vol.15 (16), p.5519-5528
• Main Authors: Mackman, Richard L., Zhang, Lijun, Prasad, Vidya, Boojamra, Constantine G., Douglas, Janet, Grant, Deborah, Hui, Hon, Kim, Choung U., Laflamme, Genevieve, 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; Anti-HIV Agents - toxicity; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Biological and medical sciences; Cell Line; Drug Resistance, Viral - drug effects; Magnetic Resonance Spectroscopy; Medical sciences; Methane - chemistry; Molecular Structure; Nucleosides; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - toxicity; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Pharmacology. Drug treatments; Phosphonates; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Resistance; Thymidine - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.05.047

Phosphonomethoxy nucleoside analogs of the nucleoside reverse transcriptase inhibitors AZT, d4T, and 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 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 μM, whereas, phosphonomethoxy analogs of ddT, 7 (ddTP), and AZT, 6 (AZTP), were both inactive at concentrations up to 200 μM. 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.