Synthesis of 4′-cyanothymidine and analogs as potent inhibitors of HIV.

O-Yang, Counde; Wu, Helen Y.; Fraser-Smith, Elizabeth B.; Walker, K.

doi:10.1016/s0040-4039(00)77667-2

Cited by 135 publications

(54 citation statements)

References 11 publications

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“…Furthermore, these compounds can even delay the onset of resistance; such a delay might result from the decreased viral load during treatment. In the search for a new antiviral compounds, others have looked at 4Ј-substituted dThd analogs (32,35), while we synthesized a series of 2Ј,3Ј-didehydro-3Ј-deoxy-4Ј-substituted thymidine (4Ј-substituted D4T) analogs. Screening revealed the 4Ј-ethynyl D4T to be the most active compound among those tested (19).…”

Section: Human Immunodeficiency Virus (Hiv [Aids]mentioning

confidence: 99%

Novel 4′-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity

Dutschman

Grill

Gullen

et al. 2004

Antimicrob Agents Chemother

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The antiviral drug 2,3-didehydro-3-deoxythymidine (D4T; also know as stavudine and Zerit), which is used against human immunodeficiency virus (HIV), causes delayed toxicity (peripheral neuropathy) in long-term use. After examining a series of 2,3-didehydro-3-deoxy-4-substituted thymidine (4-substituted D4T) analogs, 4-ethynyl D4T was found to have a fivefold-better antiviral effect and to cause less cellular and mitochondrial toxicity than D4T. The antiviral activity of this compound can be reversed by dThd but not by dCyd. The compound acted synergistically with ␤-L-2,3-deoxy-3-thiacytidine (also known as lamivudine) and ␤-L-2,3-dideoxy-2,3-didehydro-5-fluorocytidine (also known as elvucitabine) and additively with 2,3-dideoxyinosine (also known as didanosine and Videx) and 3-azido-3-deoxythymidine (also known as Retovir and zidovudine) against HIV. 4-Ethynyl D4T is phosphorylated by purified human thymidine kinase 1 (TK-1) from CEM cells with a faster relative V max and a lower K m value than D4T. The efficiency of TK-1 in the phosphorylation of 4-ethynyl D4T is fourfold better than that of D4T. While D4T is broken down by the catabolic enzyme thymidine phosphorylase, the level of breakdown of 4-ethynyl D4T was below detection. Since 4-ethynyl D4T has increased anti-HIV activity and decreased toxicity and interacts favorably with other currently used anti-HIV drugs, it should be considered for further development as an anti-HIV drug.

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Section: Human Immunodeficiency Virus (Hiv [Aids]mentioning

confidence: 99%

Novel 4′-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity

Dutschman

Grill

Gullen

et al. 2004

Antimicrob Agents Chemother

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“…18 We thought of introducing the hydroxymethyl group at the 4′ -position of the cyclopentene ring through the aldehyde 9, using in tandem, an aldol and a Cannizzaro reaction. 19 Oxidation of the hydroxymethyl group of 8 under Swern conditions 20 resulted in a mixture of products which could not be identified. The oxidation of alcohol 8 using Moffatt conditions (DCC, DMSO, DCAA) was then investigated with good results.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and antiviral evaluation of 2-amino-1,6-dihydro-6-oxo-9-[4-bis(hydroxymethyl) -2-cyclopenten-1-yl]-9H-purine: an analog of the anti-HIV compound Carbovir

Sharma

Nair²

2000

Arkivoc

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A novel carbovir analog, (±)-2-amino-1,6-dihydro-6-oxo-9-[4-bis(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purine, was synthesized starting from the γ-lactam, 2-azabicyclo [2.2.1]hept-5-en-3-one (7). The key intermediate, 1-acetamido-4-bis(hydroxymethyl)cyclopent-2-ene (10), was prepared by the Pfitzner-Moffatt oxidation of the hydroxymethyl group of 8, aldol condensation of the resulting aldehyde, followed by a Cannizzaro reaction. The guanine base was constructed on the amino group of 10. The structures of the target molecule and the intermediates were confirmed by NMR, UV and HRMS data. Anti-HIV evaluation results are reported.

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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: 88%

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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Synthesis of 4′-cyanothymidine and analogs as potent inhibitors of HIV.

Cited by 135 publications

References 11 publications

Novel 4′-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity

Novel 4′-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity

Synthesis and antiviral evaluation of 2-amino-1,6-dihydro-6-oxo-9-[4-bis(hydroxymethyl) -2-cyclopenten-1-yl]-9H-purine: an analog of the anti-HIV compound Carbovir

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

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