Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

Pertusati, Fabrizio; Serpi, Michaela; McGuigan, Christopher

doi:10.3851/imp2012

Cited by 98 publications

(80 citation statements)

References 84 publications

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“…Thus, these groups facilitate transport across cell membranes and improve the pharmacological properties of the ANPs. 16,17 In agreement with the literature, we have observed that the preparation of various types of prodrugs of the parent ANP-based inhibitors can significantly improve the activity in cell-based antimalarial assays. 13,15 As a prodrug of choice, we have selected compounds with a phosphoramidate linkage 18 having two identical amino acid esters attached, to facilitate entry into the cells.…”

Section: Figsupporting

confidence: 78%

“…The selection of this particular type of phosphonate prodrug was based on our previous experience which led to an increase of membrane permeability and bioavailability for the antiviral ANPs. 16,18,23,24 In the first step of the one-pot reaction sequence, the cleavage of the phosphonate esters 2 and 3 with Me 3 SiBr in dry pyridine under argon atmosphere forms in situ the corresponding trimethylsilyl esters. In the second step, the reaction of these intermediates with ethyl (or isopropyl for 6j and 7j) (L)-phenylalanine in the presence of 2,2′-dithiodipyridine (Aldrithiol) and triphenylphosphine yielded the corresponding target bisamidates 6a, 6c, 6j and 7a, 7b, 7j and tetra-amidates 8h, 8i and 9h, 9i (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

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Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Hocková

Janeba

Naesens

et al. 2015

Bioorganic & Medicinal Chemistry

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Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors -the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC 50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads.

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Section: Figsupporting

confidence: 78%

Section: Chemistrymentioning

confidence: 99%

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Hocková

Janeba

Naesens

et al. 2015

Bioorganic & Medicinal Chemistry

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“…However, one of the reasons may be the poor, if any, efficient cellular uptake of the α-CNPs due to their highly charged nature. Cellular uptake should therefore be enhanced by designing lipophilic prodrugs of the α-CNPs neutralizing the phosphonate charge, a strategy that is applied in the clinically used drugs adefovir dipivoxil (Hepsera), tenofovir disoproxil (Viread), and tenofovir alafenamide (36,37). These attempts are currently ongoing in our laboratories.…”

Section: Discussionmentioning

confidence: 99%

Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics

Balzarini¹,

Das

Bernatchez

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polymerases have a structurally highly conserved negatively charged amino acid motif that is strictly required for Mg 2+ cation-dependent catalytic incorporation of (d)NTP nucleotides into nucleic acids. Based on these characteristics, a nucleoside monophosphonate scaffold, α-carboxy nucleoside phosphonate (α-CNP), was designed that is recognized by a variety of polymerases. Kinetic, biochemical, and crystallographic studies with HIV-1 reverse transcriptase revealed that α-CNPs mimic the dNTP binding through a carboxylate oxygen, two phosphonate oxygens, and base-pairing with the template. In particular, the carboxyl oxygen of the α-CNP acts as the potential equivalent of the α-phosphate oxygen of dNTPs and two oxygens of the phosphonate group of the α-CNP chelate Mg 2+ , mimicking the chelation by the β-and γ-phosphate oxygens of dNTPs. α-CNPs (i) do not require metabolic activation (phosphorylation), (ii) bind directly to the substrate-binding site, (iii) chelate one of the two active site Mg 2+ ions, and (iv) reversibly inhibit the polymerase catalytic activity without being incorporated into nucleic acids. In addition, α-CNPs were also found to selectively interact with regulatory (i.e., allosteric) Mg 2+ -dNTP-binding sites of nucleos(t)ide-metabolizing enzymes susceptible to metabolic regulation. α-CNPs represent an entirely novel and broad technological platform for the development of specific substrate active-or regulatory-site inhibitors with therapeutic potential. The polymerization of nucleotides by Escherichia coli DNA polymerase I represents a general model for catalytic action of nucleic acid polymerases (SI Appendix, Fig. S1) (1, 2). According to this model, there is a universal role for the Mg 2+ cation to interact with three phosphate oxygens of dNTP. The highly conserved consensus motifs in every polymerase active site consist of either aspartate or glutamate residues that chelate Mg 2+ through three additional coordination bonds during polymerization (2, 3). The crucial role of the metal cofactor and structurally conserved active site architecture in polymerases has also been demonstrated by validating Mg 2+ as a target for the design of antiviral drugs, not only against HIV RT but also, among others, against HIV integrase, HIV ribonuclease H (RNase H), and influenza-encoded endonuclease (4, 5). Hence, it should be feasible to design a universal but simplified (d)NTP mimic that binds efficiently to a wide variety of DNA/RNA polymerases.It was hypothesized that a universal nucleoside triphosphate mimic should contain three major indispensable entities: (i) a nucleobase part (i.e., to achieve optimal Watson-Crick basepairing with the template overhang), (ii) a replacement of the triphosphate moiety that should enable efficient Mg 2+ -directed coordination, and (iii) a variable linker between the nucleobase and the modified triphosphate to mimic the pentose entity present in natural (d)NTPs. For the triphosphate part, we chose an α-carboxy phosphonate entity that is chemically stable in physiolog...

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“…There are excellent revisions (Bobeck et al, 2010;De Clercq, 2011;Jordheim et al, 2013;Pertusati et al, 2012;Pradere et al, 2014;Sofia, 2011;Zawilska et al, 2013) on this subject that should be consulted for a much more precise and complete information.…”

Section: Introductionmentioning

confidence: 98%

“…Their direct delivery would provide a potential way to circumvent this limitation, but unfortunately these compounds are rapidly hydrolysed by phosphatases. To overcome this drawback, the phosphate group has been replaced with the isoelectric and isosteric phosphonate moiety, providing a chemically and enzymatically more stable derivative that can be also further phosphorylated by nucleotide kinases (Pertusati et al, 2012). For example, Adefovir (Scheme 1) is an acyclic nucleoside phosphonate active against hepatitis B virus and HIV, which exerts its activity by inhibiting the enzyme reverse transcriptase (RT).…”

Section: Introductionmentioning

confidence: 99%