Synthetic Routes to a Series of Proximal and Distal 2′-Deoxy Fleximers

Wauchope, Orrette R.; Velasquez, Melvin S.; Seley‐Radtke, Katherine L.

doi:10.1055/s-0032-1316791

Cited by 19 publications

(18 citation statements)

References 21 publications

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“…In parallel, the organometallic coupling reagent 7 was synthesized starting from the commercially available 2-amino-4-methoxypyrimidine. 27 , 28 Stille coupling of 7 to 5 gave 1 . Alternatively, using the acetylated 6 , Stille coupling provided the desired double prodrug 2 .…”

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confidence: 99%

Flex-nucleoside analogues – Novel therapeutics against filoviruses

Yates

Raje

Chatterjee

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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Fleximers, a novel type of flexible nucleoside that have garnered attention due to their unprecedented activity against human coronaviruses, have now exhibited highly promising levels of activity against filoviruses. The Flex-nucleoside was the most potent inhibitor against recombinant Ebola virus in Huh7 cells with an EC50 = 2 μM, while the McGuigan prodrug was most active against Sudan virus-infected HeLa cells with an EC50 of 7 μM.

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confidence: 99%

Flex-nucleoside analogues – Novel therapeutics against filoviruses

Yates

Raje

Chatterjee

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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“…For some time, the Seley-Radtke group has designed and synthesized various classes of flexible purine nucleos(t)ides, or “fleximers”. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 These novel nucleosides were designed to investigate how flexibility in the nucleobase could potentially affect receptor-ligand recognition and function. In addition, their flexible design allows them to overcome issues with binding site mutations thus retaining their activity.…”

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confidence: 99%

Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

Lopresti

Shirley

et al. 2019

Bioorganic & Medicinal Chemistry

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A B S T R A C TAnti-HIV-1 drug design has been notably challenging due to the virus' ability to mutate and develop immunity against commercially available drugs. The aims of this project were to develop a series of fleximer base analogues that not only possess inherent flexibility that can remain active when faced with binding site mutations, but also target a non-canonical, highly conserved target: the nucleocapsid protein of HIV (NC). The compounds were predicted by computational studies not to function via zinc ejection, which would endow them with significant advantages over non-specific and thus toxic zinc-ejectors. The target fleximer bases were synthesized using palladium-catalyzed cross-coupling techniques and subsequently tested against NC and HIV-1. The results of those studies are described herein.

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“…These unique nucleoside analogues have been termed “fleximers” and were designed to explore how nucleobase flexibility affects the recognition, binding, and activity of nucleoside(tide) analogues. 11–16 The fleximers possess a purine base scaffold in which the imidazole and pyrimidine moieties are attached by a single carbon-carbon bond, rather than being “fused” as is typical for the purines (Figure 1). These analogues are designed to retain all of the requisite purine hydrogen bonding patterns while allowing the nucleobase to explore alternative binding modes.…”

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confidence: 99%

Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity

Peters

Jochmans

Wilde

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 > 3x EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 < 10 μM and a CC50 > 100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.

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Synthetic Routes to a Series of Proximal and Distal 2′-Deoxy Fleximers

Cited by 19 publications

References 21 publications

Flex-nucleoside analogues – Novel therapeutics against filoviruses

Flex-nucleoside analogues – Novel therapeutics against filoviruses

Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity

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