This review concerns acyclic nucleoside phosphonates (ANP) and describes the concept of the design of isopolar and isosteric nucleotide analogues resistant towards degradation by enzymes in vivo. It describes the development of research which led to the discovery of several structurally related potent antivirals and ultimately resulted in the development of drugs directed against HIV, HBV and DNA-virus infections in general, namely adefovir, cidofovir and tenofovir. In addition to these "classical compounds" the review describes the present development in the field of ANP, the "open-ring ANP" and discusses the present achievements, concept of prodrug design and application.
"The acyclic nucleotide analogue, tenofovir (Balzarini et al., 1993; Cihlar and Ray, 2009; Holy, 2006) is a special anti-HIV drug, because it requires only two phosphorylation steps to be activated. This is due to the fact that it is a phosphonate analogue (cf. "
[Show abstract][Hide abstract] ABSTRACT: Nucleoside analogues, used in HIV-therapy, need to be phosphorylated by cellular enzymes in order to become potential substrates for HIV reverse transcriptase. After incorporation into the viral DNA chain, because of lacking of their 3'-hydroxyl groups, they stop the elongation process and lead to the death of the virus. Phosphorylation of the HIV-drug derivative, tenofovir monophosphate was tested with the recombinant mammalian nucleoside diphosphate kinase (NDPK), 3-phosphoglycerate kinase (PGK), creatine kinase (CK) and pyruvate kinase (PK). Among them, only CK was found to phosphorylate tenofovir monophosphate with a reasonable rate (about 45-fold lower than with its natural substrate, ADP), while PK exhibits even lower, but still detectable activity (about 1000-fold lower compared to the value with ADP). On the other hand, neither NDPK nor PGK has any detectable activity on tenofovir monophosphate. The absence of activity with PGK is surprising, since the drug tenofovir competitively inhibits both CK and PGK towards their nucleotide substrates, with similar inhibitory constants, K(I) of 2.9 and 4.8 mM, respectively. Computer modelling (docking) of tenofovir mono- or diphosphate forms to these four kinases suggests that the requirement of large-scale domain closure for functioning (as for PGK) may largely restrict their applicability for phosphorylation/activation of pro-drugs having a structure similar to tenofovir monophosphate.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2012; 48(1-2). DOI:10.1016/j.ejps.2012.11.007 · 3.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cidofovir [(S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine] and (S)-HPMPA [(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine] are potent nucleoside phosphonate antiviral agents that are not orally bioavailable unless one or both of their negative charges are masked. This unit describes the synthesis of hexadecyloxypropyl esters of cidofovir and (S)-HPMPA. These prodrugs are readily absorbed after oral administration and are converted intracellularly to the corresponding diphosphates. The hexadecyloxypropyl esters of cidofovir and (S)-HPMPA are orally active in animal models of viral infection. Two synthetic strategies are employed. In the first, cyclic cidofovir is coupled to 3-hexadecyloxy-1-propanol using the Mitsunobu reaction (triphenylphosphine, DIAD), followed by basic hydrolysis of the cyclic ester. In the second, the lipid moiety is incorporated into a phosphonate synthon and a stepwise approach is used to assemble the (S)-HPMPA analog.
Current protocols in nucleic acid chemistry / edited by Serge L. Beaucage ... [et al.] 07/2007; Chapter 15:Unit 15.2. DOI:10.1002/0471142700.nc1502s29
[Show abstract][Hide abstract] ABSTRACT: A series of ester analogues of acyclic nucleotide PMPA and PMEA were synthesized as potent antiviral agents. The antiviral evaluation results indicated that bis benzyl ester prodrug of PMPA 5f and bis allyl ester prodrug of PMEA 5g exhibited potent antiviral activities. The IC(50) of 5f for HBV was 2.15 microM, and the IC(50) of 5g for HIV-1 was 1.61 microM.
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