173606-89-8Relevant academic research and scientific papers
Lipophilic &α-Hydroxybenzylphosphonates as Prodrugs of 3'-Azido-2',3'-dideoxythymidine (AZT)
Meier, Chris,Habel, Lothar W.,Balzarini, Jan,Clercq, Eric De
, p. 2195 - 2202 (2007/10/03)
The α-hydroxybenzylphosphonates 1a-1j of the antiviral drug 3'-azido-2',3'-dideoxythymidine 5 (AZT) as potential lipophilic prodrugs were readily accessible in 49percent to 87percent yield via a four-step synthetic pathway introducing the modifications in the aromatic ring system in the last step by making use of intermediate 6.All compounds 1a-1j exhibited higher partition coefficients in 1-octanol/water than AZT (5).In hydrolysis studies at pH 7.5 we observed that precursors to bioactive compounds were delivered by simple hydrolysis of the lipophilic precursors 1a-1j via two different mechanisms: the phosphonate-phosphate rearrangement leading to the benzylphosphotriesters 2 and/or the direct cleavage into the di-AZT phosphonate 6.Both compounds 2 and 6 were further degraded yielding the potentially antiviral active compounds 4 and 8, respectively.The hydrolysis pathway could be controlled by the substitution pattern in the benzylic moiety.Identical hydrolytic behavior of 1 was detected in "biological" hydrolysis kinetics by using a RPMI culture medium containing 10percent heat-inactivated fetal calf serum (FCS).The title compounds 1a-1j exhibited considerable HIV-1 and HIV-2 activity in wild-type CEM/O cells. - Keywords: AZT; Nucleoside α-hydroxybenzylphosphonates; Phosphonate-phosphate rearrangement; Prodrugs; HIV chemotherapy
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
