Carbocyclic 5′-nor “reverse” fleximers. Design, synthesis, and preliminary biological activity

Zimmermann, Sarah C.; Sadler, Joshua M.; Andrei, Gracíela; Snoeck, Robert; Balzarini, Jan; Seley‐Radtke, Katherine L.

doi:10.1039/c1md00094b

Cited by 18 publications

(12 citation statements)

References 23 publications

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“…The connectivity was via the pyrimidine ring with the five-membered ring as the appendage ( Figure 11 ) yielding the “reverse” fleximers. 27 , 45 The inspiration for this change in connectivity came from 2′-deoxy nucleoside analogues first published in 1991 by Herdewijn et al. 46 – 48 Some of these showed impressive activity against herpes simplex virus (HSV-1) and varicella zoster virus (VZV).…”

Section: Initial Resultsmentioning

confidence: 99%

Flexibility—Not just for yoga anymore!

Seley‐Radtke

2018

Antivir Chem Chemother

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Over the past few years, nucleosides have maintained a prominent role as one of the cornerstones of antiviral and anticancer therapeutics, and many approaches to nucleoside drug design have been pursued. One such approach involves flexibility in the sugar moiety of nucleosides, for example, in the highly successful anti-HIV and HBV drug tenofovir. In contrast, introduction of flexibility to the nucleobase scaffold has only more recently gained significance with the invention of our fleximers. The history, development, and some biological relevance for this innovative class of nucleosides are detailed herein.

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Section: Initial Resultsmentioning

confidence: 99%

Flexibility—Not just for yoga anymore!

Seley‐Radtke

2018

Antivir Chem Chemother

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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.…”

Section: Introductionmentioning

confidence: 99%

“…To date, fleximers have shown key advantages over the corresponding purine-base nucleosides. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 For example, the distal guanosine fleximer (Flex-G, Fig. 1 ) proved to be an inhibitor of S -adenosyl- l -homocysteine hydrolase by adapting a syn conformation, thereby placing the exocyclic amino group such that it mimicked the amino group from an adenosine nucleobase.…”

Section: Introductionmentioning

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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“…Nucleosides lacking a methylene group in the side chain have been reported and in some cases display reduced cytotoxicity [15]. The synthetic route that we have exploited, based on the hetero-Diels-Alder (HDA) cycloaddition of dienes with transient acyl nitroso moieties [16], affords “privileged structures” [17] for the synthesis of carbocyclic nucleosides [18].…”

Section: Introductionmentioning

confidence: 99%

Syntheses of Isoxazoline-Carbocyclic Nucleosides and Their Antiviral Evaluation: A Standard Protocol

Quadrelli

Martinez

Scrocchi

et al. 2014

The Scientific World Journal

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The current synthesis of racemic purine and pyrimidine isoxazoline-carbocyclic nucleosides is reported, detailing the key-steps for standard and reliable preparations. Improved yields were obtained by the proper tuning of the single synthetic steps, opening the way for the preparation of a variety of novel compounds. Some of the obtained compounds were also evaluated against a wide variety of DNA and RNA viruses including HIV. No specific antiviral activity was observed in the cases at hand. Novel compounds were prepared for future biological tests.

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Carbocyclic 5′-nor “reverse” fleximers. Design, synthesis, and preliminary biological activity

Cited by 18 publications

References 23 publications

Flexibility—Not just for yoga anymore!

Flexibility—Not just for yoga anymore!

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

Syntheses of Isoxazoline-Carbocyclic Nucleosides and Their Antiviral Evaluation: A Standard Protocol

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