Squalenoyl nucleoside monophosphate nanoassemblies: New prodrug strategy for the delivery of nucleotide analogues

• Published in: Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (9), p.2761-2764
• Main Authors: Caron, Joachim, Reddy, L. Harivardhan, Lepêtre-Mouelhi, Sinda, Wack, Séverine, Clayette, Pascal, Rogez-Kreuz, Christine, Yousfi, Rahima, Couvreur, Patrick, Desmaële, Didier
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor agents; Antiviral agents; Biological and medical sciences; Cell Line, Tumor; General aspects; Human immunodeficiency virus; Medical sciences; Mice; Nanoassemblies; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Nucleotides; Particle Size; Pharmacology. Drug treatments; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Squalene - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.070

Nanoassemblies of squalenoyl prodrug of ddC-MP and dFdC-MP exhibit promising biological activities. 4-( N)-1,1′,2-Trisnor-squalenoyldideoxycytidine monophosphate (SQddC-MP) and 4-( N)-1,1′,2-trisnor-squalenoylgemcitabine monophosphate (SQdFdC-MP) were synthesized using phosphoramidite chemistry. These amphiphilic molecules self-assembled to about hundred nanometers size nanoassemblies in aqueous medium. Nanoassemblies of SQddC-MP displayed significant anti-HIV activity whereas SQdFdC-MP nanoassemblies displayed promising anticancer activity on leukemia cells. These results suggested that squalene conjugate of negatively charged nucleotide analogues efficiently penetrated within cells. Thus, we propose a new prodrug strategy for improved delivery of nucleoside analogues to ameliorate their biological efficacy.