[d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor

Hunter, Roger; Muhanji, Clare I.; Hale, Ian; Bailey, Christopher M.; Basavapathruni, Aravind; Anderson, Karen S.

doi:10.1016/j.bmcl.2007.01.107

Cited by 12 publications

(12 citation statements)

References 24 publications

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“…Subsequent Sonogashira coupling with the monopropargyl ether of 4-PEG-diol 47 gave tethered TMC-derivative 4 , followed by hydroxyl group propargylation to give 5 , which was subjected to a further Sonogashira coupling with 5′-benzoyl-5-iodo-d4U 48 to afford bifunctional benzoate ( 1a ) in around 60% isolated yield. Deprotection of 1a with sodium methoxide, quenching with acetic acid, and direct silica-gel flash chromatography without a workup afforded bifunctional nucleoside, d4T-4PEG-TMC ( 1b ).…”

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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“…Thus, based on these ideas and coupled with results from the earlier work mentioned previously,16, 17 we thought it feasible that a tethered [d4U]-spacer-[HI-236] might exit the pocket into the solvent channel close to Glu13821 (p51 sub-unit shown in Figure 3) and preferably closer to Tyr181 rather than Val179. On the assumption that the NNRTI would bind first, the NRTI of the double-drug would have to make its way to the substrate-binding site around the corner behind the hydrophobic back of the NNRTI pocket near to the conserved Trp229.…”

Section: Double-drug Design Aspectsmentioning

confidence: 63%

“…For the right-hand tethered derivatives 7 , the synthesis started with commercially available 2-hydroxy-5-methoxybenzaldehyde 1 , which following a three-step sequence described by Glennon16, 22 involving phenolic hydroxyl protection with benzyl, a Henry aldol reaction and LAH-mediated reduction of both the double bond and the nitro group afforded amine 2 in gram quantities, Scheme 1. For practical reasons it was easier to isolate 2 as its N -Boc derivative 3 via a standard Boc protection step without using DMAP, which promoted di-Boc derivatisation.…”

Section: Chemistrymentioning

confidence: 99%

“…Recently, we have reported on our own efforts in the field of non-cleavable HIV double drugs using a d4U / HI-236 system. Our first prototype16 with a relatively short butynyl tether against HIV-1 (IIIB) in MT-2 cell culture using an MTT assay returned an EC50 of 250nM. This was only a fivefold reduction of the NNRTI (HI-236) EC 50 and eightfold more potent than d 4 T (2 μM).…”

Section: Introductionmentioning

confidence: 95%

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[d4U]-Spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase

Younis

Hunter

Muhanji

et al. 2010

Bioorganic & Medicinal Chemistry

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Four double-drug HIV NRTI / NNRTI inhibitors 15a-d of the type [d4U]-spacer- in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U's benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a-c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b-d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer.

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“…Recently, the Hunter and Anderson groups have reported [35] the synthesis of a non-cleavable [d4U]-butyne-[HI-236] bifunctional using a Sonogashira coupling strategy similar to that 64 using DIEA as a base and tetrazole as an activating agent, which was followed by oxidation with tert-butylhydroperoxide to give 66 as a mixture of two diastereomers based on the stereogenicity at phosphorus, in 38% overall yield for the 3 steps (Scheme 16). The double-prodrug 66 had good activities against HIV-1 (EC 50 = 0.03 µM) and the Y181C mutant strain (EC 50 = 2.7 µM).…”

Section: Nrti/nnrti Heterodimersmentioning

confidence: 98%

Current Developments in the Synthesis and Biological Activity of HIV-1 Double-Drug Inhibitors

Muhanji

Hunter²

2007

CMC

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A combination of different HIV inhibitors into a single molecular entity is a strategy that is growing in popularity in HIV-chemotherapy research. The high levels of resistance elicited by both nucleoside and non-nucleoside reverse transcriptase inhibitors has prompted the design of double-drugs combining these two entities with the aim of addressing the emergence of resistance. The strategy involves combining two different inhibitors into a single chemical entity via a linker, with the aim of improving the physicochemical characteristics of the individual compounds. Linkers may be sub-divided into cleavable and non-cleavable. While the former result in regeneration of the parent drugs of the double-drug once in the cell cytoplasm, the latter type is designed to allow the double-drug to target two active sites in a simultaneous or bifunctional fashion, which are located in close proximity. The linkers have been attached at the C-5', C-5 or N-3 positions of the nucleoside, and in some of the substrates synthesized, a synergistic anti-HIV activity has been observed. This review focuses on the design and synthesis of anti-HIV double-drugs reported to date.

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[d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor

Cited by 12 publications

References 24 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

[d4U]-Spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase

Current Developments in the Synthesis and Biological Activity of HIV-1 Double-Drug Inhibitors

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