Nucleosides and nucleotides. 183. Synthesis of 4′ α-branched thymidines as a new type of antiviral agent

Sugimoto, Isamu; Shuto, Satoshi; Mori, Shuichi; Shigeta, Shirô; Matsuda, Akira

doi:10.1016/s0960-894x(99)00010-4

Cited by 86 publications

(53 citation statements)

References 12 publications

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“…We designed and synthesized more than 20 novel 4Ј-substituted nucleoside analogs (16,27,28,38) and tested them for in vitro activity against HIV-1 by using the MTT colorimetric assay employing MT-4 cells. A thymidine analog, 4Ј-ethynyl (E)-T, and a uracil analog, 4Ј-E-IdU, were found to be moderately active against HIV-1 LAI , with EC 50 s of 0.83 and 0.29 M, respectively ( Table 1).…”

Section: Activity Of 4-substituted Nucleosides Against Hiv-1 In Vitromentioning

confidence: 99%

“…Subsequently, Chen and colleagues (4) reported that 4Ј-AZT was active against HIV-1 through its DNA chain-terminating activity. More recently, Sugimoto et al have reported that 4Ј-substituted nucleosides including 4Ј-ethynylthymidine exhibited potent activity against not only HIV-1, but also herpes simplex virus type 1 (38). We recently designed and synthesized a series of 4Ј-ethynyl (4Ј-E)-2Ј-deoxynucleosides and their analogs and identified several highly potent anti-HIV-1 compounds, including 4Ј-E-2Ј-deoxycytidine (4Ј-E-dC), 4Ј-E-2Ј-deoxyadenosine (4Ј-E-dA), 4Ј-E-2Ј-deoxyribofuranosyl-2,6-diaminopurine (4Ј-E-dDAP), and 4Ј-E-2Ј-deoxyguanosine (4Ј-E-dG).…”

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confidence: 99%

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4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

Kodama

Kohgo

Kitano

et al. 2001

Antimicrob Agents Chemother

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A series of 4′-ethynyl (4′-E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4′-E-2′-deoxycytidine (4′-E-dC), 4′-E-2′-deoxyadenosine (4′-E-dA), 4′-E-2′-deoxyribofuranosyl-2,6-diaminopurine, and 4′-E-2′-deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 μM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4′-E analogs also suppressed replication of various drug-resistant HIV-1 clones, including HIV-1M41L/T215Y, HIV-1K65R, HIV-1L74V, HIV-1M41L/T69S-S-G/T215Y, and HIV-1A62V/V75I/F77L/F116Y/Q151M. Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4′-E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1Y181C, and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4′-E-thymidine and 4′-E-dC was blocked by the addition of thymidine and 2′-deoxycytidine, respectively, while that of 4′-E-dA was not affected by 2′-deoxyadenosine, similar to the antiviral activity reversion feature of 2′,3′-dideoxynucleosides, strongly suggesting that 4′-Eanalogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4′-E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.

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Section: Activity Of 4-substituted Nucleosides Against Hiv-1 In Vitromentioning

confidence: 99%

mentioning

confidence: 99%

4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

Kodama

Kohgo

Kitano

et al. 2001

Antimicrob Agents Chemother

Self Cite

129

126

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“…Nucleosides play a major role in combating tumors and viruses, with modifications of natural nucleosides leading to novel antitumor and/or antiviral agents, including branched nucleosides such as DMDC, 1 CNDAC, 2 ECyd, 3 4'α-C-ethenylthymidine, 4 and 4'α-C-ethynylthymidine 5 as potent antiviral or antitumor agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiviral Evaluation of 1'-Branched-5'-Norcarbocyclic Adenosine Phosphonic Acid Analogues

Yoo²,

Hong³

2010

Bulletin of the Korean Chemical Society

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“…Extensive structure-activity studies found that other 4'-position lipophilic substituents, such as 4'-ethylthymidine (2), 2 also exhibited high antiviral activity against HIV. Molecular modeling studies demonstrated the presence of a narrow, relatively hydrophobic 4'-pocket that can accommodate these substitutions, contributing to enhanced potency.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti-HIV Activity of Novel 4'-Ethyl-5'-norcarbocyclic Adenosine Phosphonic Acid Analogues

Yoo¹,

Li²,

Lee³

et al. 2010

Bulletin of the Korean Chemical Society

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Nucleosides and nucleotides. 183. Synthesis of 4′ α-branched thymidines as a new type of antiviral agent

Cited by 86 publications

References 12 publications

4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

Synthesis and Antiviral Evaluation of 1'-Branched-5'-Norcarbocyclic Adenosine Phosphonic Acid Analogues

Synthesis and Anti-HIV Activity of Novel 4'-Ethyl-5'-norcarbocyclic Adenosine Phosphonic Acid Analogues

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