Synthesis and Anti-Hiv Activity of [D4u]-[Trovirdine Analogue] and [D4t]-[Trovirdine Analogue] Heterodimers as Inhibitors of Hiv-1 Reverse Transcriptase

Gavriliu, D.; Fossey, Christine; Ciurea, A.; Delbederi, Z.; Sugeac, E.; Laduree, D.; Schmidt, Sylvie; Laumond, Géraldine; Aubertin, Anne-Marie

doi:10.1081/ncn-120015066

Cited by 13 publications

(8 citation statements)

References 38 publications

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“…24,25,40–43 Moreover, earlier attempts to show efficient HIV replication inhibition of bifunctional compounds all failed. 44,45 We hypothesized that one of the possible reasons for these unsuccessful attempts could be impaired phosphorylation of the nucleoside end of bifunctional analogues catalyzed by cellular kinases. Consequently, the synthesis of a metabolically active triphosphate form of our d4T-4PEG-TMC bifunctional nucleoside was conducted to directly address the phosphorylation requirement for in vitro incorporation assays catalyzed by HIV-1 RT.…”

Section: Resultsmentioning

confidence: 99%

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Bailey

Sullivan²,

Iyidogan³

et al. 2013

J. Med. Chem.

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Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.

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Section: Resultsmentioning

confidence: 99%

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Bailey

Sullivan²,

Iyidogan³

et al. 2013

J. Med. Chem.

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show abstract

“…However, replacement of the 5'-[(tert-butyl)dimethylsilyl] (TBDMS) group by alkyl, alkenyl, or aromatic ether groups, substituted amines, carbamoyl or (thio)acyl groups markedly diminished or even annihilated anti-HIV activity [81]. A similar heterodimer, [Trovirdine]-(CH 2 ) 3 -[d4T], however, was reported to be inactive against HIV-1 replication [84]. However, the [TSAO-T]-(CH 2 ) 3 -[d4T] heterodimer derivative (Fig.…”

mentioning

confidence: 99%

Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Past, Present, and Future

Clercq¹

2004

Chemistry & Biodiversity

231

165

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Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent ingredient of the drug combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. Starting from the 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine (HEPT) and 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives, numerous classes of compounds have been described as NNRTIs. Only three compounds have so far been approved for clinical use: nevirapine, delavirdine, and efavirenz. NNRTIs are notorious for rapidly leading to virus-drug resistance development, primarily based on the emergence of the K103N and Y181C mutations in the HIV-1 RT. Newer NNRTIs, such as capravirine, dapivirine (TMC 125), and DPC 083, are resilient to these 'NNRTI' mutations, and, therefore, offer considerable promise as future anti-HIV-1 drugs. NNRTIs are targeted at a specific 'pocket' binding site within the HIV-1 RT, that is distinct from, but both spatially and functionally related to, the catalytic site, where the nucleoside RT inhibitors (NRTIs) and nucleotide RT inhibitors (NtRTIs) interact. NNRTIs have acquired a definitive position, as part of a combination regimen with NRTIs and NtRTIs, in the first-line treatment of HIV-1 infections.

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“…The facile synthesis of aminooxoethylcarbamothionates may turn out to be an important route to the potential HIV‐1 transcriptase inhibitors, because this motif was found to be a privileged structure in a series of compounds exhibiting such an antiviral activity . We will further investigate the ways of generalization of such unusual termolecular decyclization reaction, aiming at the synthesis of libraries of potential pharmaceuticals.…”

Section: Resultsmentioning

confidence: 99%

A Controlled Cyclization of Functionalized Thioureas and Unprecedented Termolecular Decyclization of Iminothiazolidinones

et al. 2019

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A series of thiourea derivatives bearing pendant hydroxyl groups was synthesized. These quadruply nucleophilic compounds underwent cyclization reactions with bromoacyl bromides, yielding two isomeric iminothiozolidinones. While the remote hydroxyl group in functionalized thioureas was not directly involved in the cyclization, it allowed us to establish control over the product formation through the choice of temperature and/or solvent. The new mode of temperature‐dependent control over the product distribution was different from the classical kinetic vs thermodynamic control. A number of synthesized iminothiozolidinones underwent an unprecedented termolecular decyclization reaction in the presence of an external nucleophile and a proton to yield aminooxoethylcarbamothionates. In addition to the theoretical importance of this newly discovered reaction, there is also a practical need for these decyclized products as they are known privileged structures in the family of HIV‐1 transcriptase inhibitors.

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Synthesis and Anti-Hiv Activity of [D4u]-[Trovirdine Analogue] and [D4t]-[Trovirdine Analogue] Heterodimers as Inhibitors of Hiv-1 Reverse Transcriptase

Cited by 13 publications

References 38 publications

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Past, Present, and Future

A Controlled Cyclization of Functionalized Thioureas and Unprecedented Termolecular Decyclization of Iminothiazolidinones

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