Structure-Activity Relationships Among HIV Inhibitory 4′-Substituted Nucleosides

Prisbe, Ernest J.; Maag, Hans; Verheyden, Julien P. H.; Rydzewski, Robert M.

doi:10.1007/978-1-4615-2824-1_5

Cited by 20 publications

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References 22 publications

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“…Until now, many 4′-substituted nucleosides have been synthesized (for an excellent review: Hayakawa et al, 2004) with the aim of developing new anti-HIV-1 agents with efficacy against drug-resistant mutants. However, such synthetic efforts have been focused on 2′-deoxyribonucleoside analogues, due to the disclosure of a structure-activity relationship study of 4′-azidothymidine (Prisbe et al, 1993) suggesting that the presence of the 3′-hydroxyl group is indispensable for the 4′-substituted nucleoside to be active against HIV-1: both the 3′-deoxy and 2′,3′-didehydro-3′-deoxy derivatives were devoid of the activity.In our recent studies (Haraguchi et al, 2003a and2003b) aiming at the development of new synthetic methodology for 4′-substituted nucleosides, various types of 4′-carbon-substituted nucleosides were synthesized. Among these compounds, 4′-ethynylstavudine (4′-Ed4T) (Figure 1) was found to be more active than its parent compound stavudine (d4T).…”

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confidence: 98%

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Pointer 4'-Ethynylstavudine (4'-Ed4T) Has Potent Anti-HIV-1 Activity with Reduced Toxicity and Shows a Unique Activity Profile against Drug-Resistant Mutants

Tanaka

Haraguchi

Kumamoto

et al. 2005

Antivir Chem Chemother

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A nucleoside analogue 4'-ethynylstavudine (4'-Ed4T) was recently synthesized during chemical studies directed towards the development of a new route to 4'-carbon-substituted nucleosides. This compound was found to be more anti-HIV-1 active than the parent compound stavudine (d4T) and much less toxic to various cells and also to mitochondrial DNA synthesis. It became apparent that 4'-Ed4T is a better substrate for human thymidine kinase than d4T, and very much more resistant to catabolism by thymidine phosphorylase. The study of 4'-Ed4T against various drug-resistant HIV-1 mutants has disclosed its unique activity profile.

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confidence: 98%

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confidence: 98%

Pointer 4'-Ethynylstavudine (4'-Ed4T) Has Potent Anti-HIV-1 Activity with Reduced Toxicity and Shows a Unique Activity Profile against Drug-Resistant Mutants

Tanaka

Haraguchi

Kumamoto

et al. 2005

Antivir Chem Chemother

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“…The 2Ј,3Ј-dideoxy and the 2Ј,3Ј-dideoxy-2Ј,3Ј-didehydro classes of nucleoside analogues have given rise to zidovudine (AZT), the first drug approved for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infections (12). Together with other members of this class of nucleoside analogues, including stavudine (d4T) (24), didanosine (ddI) (21), zalcitabine (ddC) (30), the heterosubstituted nucleoside lamivudine (3TC) (1,2,22,27), and more recently, the carbocyclic analogue 1592U89 (abacavir) (29), these classes of nucleoside analogues continue to represent a major chemotherapeutic approach to the management of HIV-1 infections, the causative agent of AIDS. However, despite the number of HIV-1 reverse transcriptase (RT) inhibitors available for clinical use at the present time and the effectiveness of administration of nucleoside RT inhibitors in combination with nonnucleoside RT inhibitors and protease inhibitors, long-term exposure of the patient to these drugs often results in the development of viral resistance or intolerance to the antiviral chemotherapy regimens.…”

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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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“…While we were working on our project, the anti-HIV activity of several 4'SdNs was reported by the Syntex group [16][17][18][19][20][21][22] and others [23,24]. Therefore, the anti-HIV activities of 4'SdNs that we studied together with those reported by other groups are listed in Table 2.…”

Section: Structure-activity Relationship (Sar) Of 4'sdnsmentioning

confidence: 87%

A New Paradigm for Developing Antiviral Drugs Exemplified by the Development of Supremely High Anti-HIV Active EFdA

Ohrui¹

2014

J Antivir Antiretrovir

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Structure-Activity Relationships Among HIV Inhibitory 4′-Substituted Nucleosides

Cited by 20 publications

References 22 publications

Pointer 4'-Ethynylstavudine (4'-Ed4T) Has Potent Anti-HIV-1 Activity with Reduced Toxicity and Shows a Unique Activity Profile against Drug-Resistant Mutants

Pointer 4'-Ethynylstavudine (4'-Ed4T) Has Potent Anti-HIV-1 Activity with Reduced Toxicity and Shows a Unique Activity Profile against Drug-Resistant Mutants

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

A New Paradigm for Developing Antiviral Drugs Exemplified by the Development of Supremely High Anti-HIV Active EFdA

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