Nucleoside diphosphate prodrugs.
Nucleoside analogs are widely applied in antiviral and antitumor therapy. A severe limitation of these compounds arises from the need of biotransformation to the eventually active nucleoside triphosphates by stepwise addition of phosphate by kinases. This problem can be circumvented by employing reversibly masked nucleotides (prodrugs). However, the known concepts to bypass enzyme activation have almost exclusively been applied to nucleoside monophosphates. Here, we report on the transfer of the bis-(acyloxybenzyl)-concept (BAB-concept) from nucleoside monophosphates to nucleoside diphosphates (NDP) of the anti HIV drugs AZT and d4T. After successful synthesis and isolation of the compounds (BAB-NDPs), it was shown that these compounds exhibit promising hydrolytic properties ranging from high stability at physiological pH to very low stability in cellular extracts. Furthermore, we demonstrated that for some of the compounds a selective cleavage mechanism resulted in the exclusive delivery of the corresponding nucleoside diphosphate within 15 minutes without any degradation of the pyrophosphate unit, which is a unique result in the field of NDP-prodrugs.
Meier
C
C
Organic Chemistry, Department of Chemistry, Faculty of Science, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany. chris.meier@chemie.uni-hamburg.de
Jessen
H J
HJ
Balzarini
J
J
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism; D011756:Diphosphates / Q000737:chemistry*; D006868:Hydrolysis; D009705:Nucleosides / Q000737:chemistry* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism; D013942:Thymine Nucleotides / Q000737:chemistry / Q000378:metabolism; D015215:Zidovudine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
D019380:Anti-HIV Agents; D011756:Diphosphates; D009705:Nucleosides; D011355:Prodrugs; D013942:Thymine Nucleotides; C541613:bis(4-acetoxybenzyl)zidovudine diphosphate; D015215:Zidovudine