Phosphonylalkoxyalkyl and Phosphonylalkyl Derivatives of Heterocyclic Bases

Holy, A.; Rosenberg, Ivan

doi:10.1080/07328318908054207

Cited by 5 publications

(2 citation statements)

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“…The synthesis of 3 − 6 required gram quantities of 1 as the starting marterial. Of several reported routes ,− to 1 from cytosine, that briefly described by Brodfuehrer et al offers advantages of economy and efficiency. The method begins with regiospecific alkylation of N -benzoyl cytosine with ( S )-2-trityloxymethyloxirane and subsequent reaction of the benzoylated cytosine intermediate with diethyl tosylmethylphosphonate, detritylation with HCl, conversion to the phosphonic acid via bromotrimethylsilane (BTMS) silylation−dealkylation, and finally NH 4 OH treatment to remove the benzoyl protecting group.…”

Section: Resultsmentioning

confidence: 99%

Serine Peptide Phosphoester Prodrugs of Cyclic Cidofovir: Synthesis, Transport, and Antiviral Activity

et al. 2008

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Cidofovir (HPMPC, 1), a broad-spectrum antiviral agent, is currently used to treat AIDS-related human cytomegalovirus (HCMV) retinitis and has recognized therapeutic potential for orthopox virus infections, but is limited by its low oral bioavailability. Cyclic cidofovir (2) displays decreased nephrotoxicity compared to 1, while also exhibiting potent antiviral activity. Here we describe in detail the synthesis and evaluation as prodrugs of four cHPMPC dipeptide conjugates in which the free POH of 2 is esterified by the Ser side chain alcohol group of an X-L-Ser(OMe) dipeptide: 3 (X = L-Ala), 4 (X = L-Val), 5 (X = L-Leu), and 6 (X = L-Phe). Perfusion studies in the rat establish that the mesenteric permeability to 4 is more than 30-fold greater than to 1, and the bioavailability of 4 is increased 8-fold relative to 1 in an in vivo murine model. In gastrointestinal and liver homogenates, the cHPMPC prodrugs are rapidly hydrolyzed to 2. Prodrugs 3, 4, and 5 are nontoxic at 100 μM in HFF and KB cells and in cell-based plaque reduction assays had IC 50 values of 0.1-0.5 μM for HCMV and 10 μM for two orthopox viruses (vaccinia and cowpox). The enhanced transport properties of 3-6, conferred by incorporation of a toxicologically benign dipeptide moiety, and the facile cleavage of the Ser-O-P linkage suggest that these prodrugs represent a promising new approach to enhancing the bioavailability of 2.

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Section: Resultsmentioning

confidence: 99%

Serine Peptide Phosphoester Prodrugs of Cyclic Cidofovir: Synthesis, Transport, and Antiviral Activity

et al. 2008

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“…Our systematic study on the synthesis and biological properties of the nucleoside phosphonic acids and related compounds provided a number of structurally diverse isopolar nucleotide analogues . Among them, a seven-membered nucleoside phostone was prepared by intramolecular esterification of adenosine-5‘- O -methylphosphonic acid …”

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confidence: 99%