Design and synthesis of unprecedented 9- and 10-membered cyclonucleosides with PRMT5 inhibitory activity

Design and synthesis of unprecedented 9- and 10-membered cyclonucleosides with PRMT5 inhibitory activity

[Display omitted] Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5′-cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors....

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry Vol. 66; p. 116820
Main Authors: Kawamura, Shuhei, Palte, Rachel L., Kim, Hai-Young, Saurí, Josep, Sondey, Christopher, Mansueto, My S., Altman, Michael D., Machacek, Michelle R.
Format: Journal Article
Language:English
Published: England Elsevier Ltd 15-07-2022
Subjects:
Cyclonucleoside
Medicinal chemistry
Molecular modeling
Nucleoside
PRMT5
PRMT5 inhibitor
X-ray crystallography
DIEA
Medicinal chemistry
Ac
EDC
TFA
Et
X-ray crystallography
SFC
THF
DPEN
Molecular modeling
DBU
IC50
DMAP
Nucleoside
NBS
Ts
PRMT5
PRMT5 inhibitor
TBS
DIBAL
MW
TBAF
NIS
HOAt
TEMPO
DTBP
Cyclonucleoside
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Summary:[Display omitted] Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5′-cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2022.116820