Total Synthesis of the Natural Product (+)‐<i>trans</i>‐Dihydronarciclasine via an Asymmetric Organocatalytic [3+3]‐Cycloaddition and discovery of its potent anti‐Zika Virus (ZIKV) Activity

Revu, Omkar; Zepeda-Velázquez, Carlos; Nielsen, Alexander J.; McNulty, James; Yolken, Robert H.; Jones‐Brando, Lorraine

doi:10.1002/slct.201601536

Cited by 19 publications

(27 citation statements)

References 52 publications

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“…Our analyses of a panel of viruses were stimulated by our prior report indicating the potency of R430 against VZV 18 , and our recent discovery that OR430, a derivative of R430, is efficacious against ZIKV 20 . Consistent with the earlier reports, we found that R430 exerts antiviral activity against RNA viruses like ZIKV (Brazilian and Cambodian strains).…”

Section: Discussionmentioning

confidence: 99%

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R430: A potent inhibitor of DNA and RNA viruses

D’Aiuto

McNulty

Hartline

et al. 2018

Sci Rep

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Acyclovir (ACV) is an effective antiviral agent for treating lytic Herpes Simplex virus, type 1 (HSV-1) infections, and it has dramatically reduced the mortality rate of herpes simplex encephalitis. However, HSV-1 resistance to ACV and its derivatives is being increasingly documented, particularly among immunocompromised individuals. The burgeoning drug resistance compels the search for a new generation of more efficacious anti-herpetic drugs. We have previously shown that trans-dihydrolycoricidine (R430), a lycorane-type alkaloid derivative, effectively inhibits HSV-1 infections in cultured cells. We now report that R430 also inhibits ACV-resistant HSV-1 strains, accompanied by global inhibition of viral gene transcription and enrichment of H3K27me3 methylation on viral gene promoters. Furthermore, we demonstrate that R430 prevents HSV-1 reactivation from latency in an ex vivo rodent model. Finally, among a panel of DNA viruses and RNA viruses, R430 inhibited Zika virus with high therapeutic index. Its therapeutic index is comparable to standard antiviral drugs, though it has greater toxicity in non-neuronal cells than in neuronal cells. Synthesis of additional derivatives could enable more efficacious antivirals and the identification of active pharmacophores.

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Section: Discussionmentioning

confidence: 99%

“…R430 also inhibited varicella zoster virus (VZV) lytic infection more potently than ACV 18 . A hydroxy analogue of R430 was recently reported to have potent activity to the Zika virus (ZIKV) 20 , suggesting that R430 and its derivatives could inhibit a spectrum of DNA and RNA viruses.…”

Section: Introductionmentioning

confidence: 99%

R430: A potent inhibitor of DNA and RNA viruses

D’Aiuto

McNulty

Hartline

et al. 2018

Sci Rep

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“…Finally, considering that many of isoquinolin‐1( 2H )‐one derivatives possess various antiviral activities [16e,f] and plant virus diseases are the second largest plant diseases which have caused great damage to agricultural industry, the anti‐tobacco mosaic virus (TMV) activities of part of the desired molecules were measured (Table 4). From the biological assay results in Table 4, in comparison with 1 a , their antiviral activity was significantly improved.…”

Section: Resultsmentioning

confidence: 99%

A Palladium(0)‐Catalyzed C4 Site‐Selective C−H Difluoroalkylation of Isoquinolin‐1(2H)‐Ones

2021

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Herein, we report a Palladium(0)‐catalyzed C4 site‐selective C−H difluoroalkylation of isoquinolin‐1(2H)‐ones through a radical pathway. The present reaction enables the preparation of 2,2‐difluoro‐2‐(1‐oxo‐1,2‐dihydroisoquinolin‐4‐yl)acetates/acetamides through the direct cross‐coupling reaction of readily available isoquinolin‐1(2H)‐ones with 2‐bromo‐2,2‐difluoroacetates or 2‐bromo‐2,2‐difluoroacetamides. Therefore, this method provides an efficient and convenient approach to install a difluoroacetate or a difluoroacetamide moiety into bioactive molecules. Bioassay results showed that introduction of these difluorinated groups at C4 position was beneficial to improve their antiviral activity and compound 5 ab was found to exhibit similar antiviral activity with commercial Ningnanmycin.

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“…Besides, strong antiviral activities of some phenanthridone alkaloids including compounds 4, 6, and 7 were reported by Gabrielsen and coworkers [33,34]. Very recently, trans-dihydronarciclasine, pancratistatin, and narciclasine have also been found to be active against Zika virus [35].…”

Section: Introductionmentioning

confidence: 87%

Stereoselective synthesis of trans-dihydronarciclasine derivatives containing a 1,4-benzodioxane moiety

et al. 2018

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Some new trans-dihydronarciclasine derivatives containing a 1,4-benzodioxane moiety were stereoselectively synthesised using our feasible and efficient method developed recently. These new phenanthridone alkaloid analogues were obtained in both racemic and optically active forms. High enantioselectivities (up to 99% ee) were achieved by applying (8S,9S)-9amino(9-deoxy)epiquinine as an organocatalyst. Due to a side reaction, various methoxyphenanthridine regioisomers were also prepared which afforded further synthetic trans-dihydronarciclasine analogues modified in the ring A of the phenanthridone scaffold. Graphical abstract

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Total Synthesis of the Natural Product (+)‐trans‐Dihydronarciclasine via an Asymmetric Organocatalytic [3+3]‐Cycloaddition and discovery of its potent anti‐Zika Virus (ZIKV) Activity

Cited by 19 publications

References 52 publications

R430: A potent inhibitor of DNA and RNA viruses

R430: A potent inhibitor of DNA and RNA viruses

A Palladium(0)‐Catalyzed C4 Site‐Selective C−H Difluoroalkylation of Isoquinolin‐1(2H)‐Ones

Stereoselective synthesis of trans-dihydronarciclasine derivatives containing a 1,4-benzodioxane moiety

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