166318-80-5Relevant academic research and scientific papers
5',5'-Di-O-nucleosyl-O'-benzylphosphotriesters as Potential Prodrugs of 3'-Azido-2',3'-dideoxythymidine-5'-monophosphate
Meier, Chris,Habel, Lothar W.,Balzarini, Jan,Clercq, Eric De
, p. 2203 - 2208 (2007/10/03)
The synthesis of 5',5'-O-di-(3'-azido-2',3'-dideoxythymidinyl)-O'-benzylphosphotriesters 1 as potential prodrugs of nucleoside monophosphates is described.The concept is applied to the antiretroviral nucleoside analog 3'-azido-2',3'-deoxythymidine (AZT) 4.All derivatives 1 were synthesized by reaction of the tetra-n-butylammonium salt of di-AZT-phosphate 2b with different benzyl bromides or -chlorides 9.Compound 2b was obtained by a combination of phosphoamidite/H-phosphonate chemistry, subsequent oxidation to 2a, and cation exchange.The partition coefficients of 1 in an 1-octanol/water mixture show that all compounds exhibit a much higher lipophilicity than the parent nucleoside AZT (4).It was also shown, that 1 decomposes spontaneously under mild aqueous basic conditions (phosphate buffer (pH 7.5) and RPMI culture medium containing heat-deactivated fetal calf serum) releasing selectivity the di-AZT phosphate anion 2.The half-lives of 1 could be adjusted within a wide range by changing the ring substituents of the benzyl group.Additionally, the mechanism of hydrolysis varies if the substituent is changed from a donor to an acceptor one.The described phosphotriesters 1 exhibit considerable antiviral activity in HIV-1- and HIV-2-infected CEM/O cells, whereas no activity was detected in the HIV-2-infected thymidine kinase-deficient CEM cell line.On the other hand, we could not detect any cytotoxicity of the described phosphotriesters.Consequently, compounds 1 should act as prodrugs or depot forms at least of antiviral nucleoside analogs. - Keywords: 5',5'-O-Di-AZT-O'-benzylphosphotriester; Homo-dinucleoside prodrugs; Anti-HIV chemotherapy; Nucleoside monophosphate
