Conformationally locked bicyclo[4.3.0]nonane carbanucleosides: synthesis and bio-evaluation

Shing, Tony K. M.; Wong, A.W.H.; Li, Yong; Liu, Z. F.; Chan, Paul K.S.

doi:10.1039/c4ob01763c

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…Saturated bicyclo-[4.3.0]-nonane nucleoside analogues provide an excellent entry for functionalization and SAR study; unfortunately, these analogues do not show antiviral activity and their synthesis is lengthy and inefficient (involving 16 to 19 synthetic steps from (d)-ribose, see Fig S1). 35 We hypothesize that an endocyclic double bond in the unsaturated bicyclo-[4.3.0]-nonene scaffold (Fig. 1C) would render them conformationally similar to the bioactive analogues entecavir and ribavirin.…”

Section: Introductionmentioning

confidence: 99%

Diversification of Nucleoside Analogues as Potent Antiviral Drug Leads

Scheeff,

Wang,

Lyu

et al. 2023

Preprint

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Nucleoside analogues are widely used as effective antiviral drugs. The continuous emergence of pathogenic viruses calls for novel and structurally diverse nucleoside analogues. Herein, we report a divergent synthesis of highly bioactive and non-cytotoxic nucleoside analogues with an unprecedented carbobicyclic core. In our step-economic synthesis, a Mitsunobu reaction and an intermolecular Diels-Alder reaction rapidly create a focused library of regio- and stereo-divergent analogues. In our evaluations against the respiratory syncytial virus, we found these analogues to be up to 16 times more potent than ribavirin, an FDA-approved antiviral nucleoside analogue. Importantly, the carbobicyclic core structure is critical for the potent antiviral activity, thus opening up ample opportunities for further lead optimization and mechanistic investigations.

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Section: Introductionmentioning

confidence: 99%

Diversification of Nucleoside Analogues as Potent Antiviral Drug Leads

Scheeff,

Wang,

Lyu

et al. 2023

Preprint

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“…Representative 1-substituted (32), 2-substituted (33), 1,2disubstituted (34), and 1,3-disusbstituted (35) dienes were found to react efficiently with a model 1,1-dichloroalkene. In the case of 1,3-disubstituted dienes (35)(36)(37)(38)(39)(40) the cycloadditions proceeded with high E selectivity (9:1 to >20:1 ratio of stereoisomers).…”

mentioning

confidence: 99%

Catalytic reductive [4 + 1]-cycloadditions of vinylidenes and dienes

Zhou

Uyeda

2019

Science

126

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Cycloaddition reactions provide direct and convergent routes to cycloalkanes, making them valuable targets for the development of synthetic methods. Whereas six-membered rings are readily accessible from Diels-Alder reactions, cycloadditions that generate five-membered rings are comparatively limited in scope. Here, we report that dinickel complexes catalyze [4 + 1]-cycloaddition reactions of 1,3-dienes. The C1partner is a vinylidene equivalent generated from the reductive activation of a 1,1-dichloroalkene in the presence of stoichiometric zinc. Intermolecular and intramolecular variants of the reaction are described, and high levels of asymmetric induction are achieved in the intramolecular cycloadditions using aC2-symmetric chiral ligand that stabilizes a metal-metal bond.

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“…The synthesis of conformationally locked nucleosides presents notable challenges, primarily due to the necessity of designing them ab initio and their high density of stereochemical information. 9 For instance, the synthesis of IIa can be achieved only through a complete total synthesis route in 8–15 synthetic steps. 8 Similarly, N-MCT IIb , another locked carbocyclic analogue, is achieved after 11 steps from the same precursor III .…”

mentioning

confidence: 99%

Design and Synthesis of Bicyclo[4.3.0]nonene Nucleoside Analogues

Scheeff,

Wang,

Lyu

et al. 2023

Org. Lett.

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Nucleoside analogues are effective antiviral agents, and the continuous emergence of pathogenic viruses demands the development of novel and structurally diverse analogues. Here, we present the design and synthesis of novel nucleoside analogues with a carbobicyclic core, which mimics the conformation of natural ribonucleosides. Employing a divergent synthetic route featuring an intermolecular Diels–Alder reaction, we successfully synthesized carbobicyclic nucleoside analogues with high antiviral efficacy against respiratory syncytial virus.

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Conformationally locked bicyclo[4.3.0]nonane carbanucleosides: synthesis and bio-evaluation

Cited by 7 publications

References 41 publications

Diversification of Nucleoside Analogues as Potent Antiviral Drug Leads

Diversification of Nucleoside Analogues as Potent Antiviral Drug Leads

Catalytic reductive [4 + 1]-cycloadditions of vinylidenes and dienes

Design and Synthesis of Bicyclo[4.3.0]nonene Nucleoside Analogues

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