The potential for using carbocyclic nucleosides for the treatment of AIDS. Part 1. Preparation of some analogues for azidothymidine (AZT)

Highcock, Rona M.; Hilpert, Hans; Myers, Peter L.; Roberts, Stanley M.; Storer, Richard

doi:10.1039/p19910001127

Cited by 19 publications

(13 citation statements)

References 13 publications

(4 reference statements)

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“…The cytosine nucleoside analogue dOTC and its enantiomers as well as 3TC were synthesized at BioChem Pharma as described previously (1,14,15). For enzyme inhibition studies and/or as controls for intracellular metabolite analysis (Ϫ)-dOTC and (ϩ)-dOTC were chemically converted into their monophosphate (MP), diphosphate (DP), or TP derivatives by the methodology reported by Highcock et al (7). The 3 H-labeled versions of (ϩ)-dOTC and (Ϫ)-dOTC (specific activities, 2.3 Ci/mmol) were obtained from International Isotopes Clearing House, while [ 3 H]3TC (specific activity, 12 Ci/mmol), 3TCphosphorylated standards, and [ 3 H]AZT (specific activity, 18.2 Ci/mmol) were purchased from Moravek Biochemicals (Brea, Calif.).…”

Section: Methodsmentioning

confidence: 99%

Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2′-Deoxy-3′-Oxa-4′-Thiocytidine

Muys

Gourdeau

Nguyen-Ba

et al. 1999

Antimicrob Agents Chemother

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The racemic nucleoside analogue 2′-deoxy-3′-oxa-4′-thiocytidine (dOTC) is in clinical development for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. dOTC is structurally related to lamivudine (3TC), but the oxygen and sulfur in the furanosyl ring are transposed. Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells. Both 5′-triphosphate (TP) derivatives of dOTC were more potent than 3TC-TP at inhibiting HIV-1 reverse transcriptase (RT) in vitro. The Ki values for dOTC-TP obtained against human DNA polymerases α, β, and γ were 5,000-, 78-, and 571-fold greater, respectively, than those for HIV RT (28 nM), indicating a good selectivity for the viral enzyme. In culture experiments, dOTC is a potent inhibitor of primary isolates of HIV-1, which were obtained from antiretroviral drug-naive patients as well as from nucleoside therapy-experienced (3TC- and/or zidovudine [AZT]-treated) patients. The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 μM, rising to only 2.53 and 2.5 μM for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively. This minimal change in activity is in contrast to the more dramatic changes observed when 3TC or AZT was evaluated against these same viral isolates. In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [3H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 μM for all cell lines tested. In addition, after 14 days of continuous culture, at concentrations up to 10 μM, no measurable toxic effect on HepG2 cells or mitochondrial DNA replication within these cells was observed. When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid.

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Section: Methodsmentioning

confidence: 99%

Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2′-Deoxy-3′-Oxa-4′-Thiocytidine

Muys

Gourdeau

Nguyen-Ba

et al. 1999

Antimicrob Agents Chemother

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“…The rationale for the synthesis of carbocyclic nucleosides in which the furanose ring oxygen of 4‘-oxonucleosides is substituted by a methylene group was to stabilize the hydrolytically and enzymatically scissile glycosyl bond with minimal structural disturbances. − However, the fact that most conventional carbocyclic nucleosides have generally exhibited poorer biological potencies than the corresponding 4‘-oxonucleosides would suggest that the conformational differences between furanose and cyclopentane rings might be partially responsible for the observed differences in biological potency. Judging from the published X-ray structures of some carbocyclic nucleosides, they appear to crystallize with an unusual ring pucker relative to 4‘-oxonucleosides. − For example, thymidine shows a characteristic 2‘-endo/3‘-exo ring pucker ( 2 T 3 ) resulting from the dominant gauche effect interaction between the 4‘-oxygen and the 3‘-hydroxyl group over the anomeric effect . Loss of the furanose oxygen in carbathymidine, however, abolishes these two effects, causing the carbocyclic ring to adopt a rare 1‘-exo pucker ( 1 E, P = 126°) .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Cyclopropyl-Fused Carbocyclic Nucleosides via the Regioselective Opening of Cyclic Sulfites

et al. 1999

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The syntheses of some carbocyclic nucleosides that are conformationally locked as "northern" mimics of antiviral active, ring-expanded oxetanocin analogues are reported. The target compounds derived their rigid conformation from a common bicyclo[3.1.0]hexane template. The uracil (3a), cytosine (3b), and adenine (3c) analogues were synthesized from an intermediate cyclic sulfite (12a) that underwent selective ring opening with nucleophiles. Reaction of 12a with sodium azide provided access to the uracil and cytosine analogues (3a and 3b) after construction of the pyrimidine rings, and reaction with the sodium salt of adenine provided an efficient convergent approach to 3c. The preponderance of the undesired N-7 regioisomer obtained from the coupling of 12a with 2-amino-6-chloropurine was unanticipated. Hence, the diol derivative 11 was selectively protected and coupled under Mitsunobu conditions to give, after deprotection, the desired guanine analogue 3d. With the exception of the guanine analogue, the cyclic sulfite chemistry described here represents a useful alternative as a general approach to carbocyclic nucleosides. None of the target nucleosides 3a-d demonstrated significant antiviral activity against HIV-1, HSV-1, HSV-2, and HCMV. Relative to other conformationally rigid, northern carbocyclic analogues that have shown good anti-HSV and anti-HCMV activities, it is concluded that the hydroxymethyl group is a poor substitute for the hydroxyl group in these rigid bicyclic nucleoside templates.

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“…" We felt that the mimicry of a 5'-monophosphate unit by a phosphonomethoxy unit could also be examined by appropriate modification of carbocyclic nucleosides such as 8 and 9 since some of these compounds display anti-HIV activity l 2 through inhibition of HIV-rt by the corresponding triphosphates. Specifically, we wished to prepare the carbocyclic compounds 10 and 11 to compare the inhibition of HIV-rt by these species with results obtained from the related compounds 2, 12 and 13 which were known to possess good to excellent inhibitory activity against this enzyme.14 We report our progress in achieving these targets.…”

mentioning

confidence: 99%

The potential of carbocyclic nucleosides for the treatment of AIDS: synthesis of some diphosphorylphosphonates possessing potent activity against HIV-coded reverse transcriptase

Coe¹,

Roberts²,

Storer³

1992

J. Chem. Soc., Perkin Trans. 1

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The potential for using carbocyclic nucleosides for the treatment of AIDS. Part 1. Preparation of some analogues for azidothymidine (AZT)

Cited by 19 publications

References 13 publications

Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2′-Deoxy-3′-Oxa-4′-Thiocytidine

Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2′-Deoxy-3′-Oxa-4′-Thiocytidine

Synthesis of Cyclopropyl-Fused Carbocyclic Nucleosides via the Regioselective Opening of Cyclic Sulfites

The potential of carbocyclic nucleosides for the treatment of AIDS: synthesis of some diphosphorylphosphonates possessing potent activity against HIV-coded reverse transcriptase

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