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

Shuhei Kawamura; Rachel L. Palte; Hai-Young Kim; Josep Sauri; Christopher Sondey; My S. Mansueto; Michael D. Altman; Michelle R. Machacek

doi:10.1016/j.bmc.2022.116820

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

Shuhei Kawamura
, Rachel L. Palte
, Hai-Young Kim
, Josep Sauri
, Christopher Sondey
, My S. Mansueto
, Michael D. Altman
, Michelle R. Machacek

Research output: Indexed journal article › Article › peer-review

9 Citations (Scopus)

Abstract

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.

Original language	English
Article number	116820
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry
Volume	66
Early online date	May 2022
DOIs	https://doi.org/10.1016/j.bmc.2022.116820
Publication status	Published - 15 Jul 2022
Externally published	Yes

Keywords

Cyclonucleoside
Medicinal chemistry
Molecular modeling
Nucleoside
Prmt5
PRMT5 inhibitor
X-ray crystallography

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10.1016/j.bmc.2022.116820

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title = "Design and synthesis of unprecedented 9-and 10-membered cyclonucleosides with PRMT5 inhibitory activity",

abstract = "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.",

keywords = "Cyclonucleoside, Medicinal chemistry, Molecular modeling, Nucleoside, Prmt5, PRMT5 inhibitor, X-ray crystallography",

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T1 - Design and synthesis of unprecedented 9-and 10-membered cyclonucleosides with PRMT5 inhibitory activity

AU - Kawamura, Shuhei

AU - Palte, Rachel L.

AU - Kim, Hai-Young

AU - Sauri, Josep

AU - Sondey, Christopher

AU - Mansueto, My S.

AU - Altman, Michael D.

AU - Machacek, Michelle R.

PY - 2022/7/15

Y1 - 2022/7/15

N2 - 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.

AB - 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.

KW - Cyclonucleoside

KW - Medicinal chemistry

KW - Molecular modeling

KW - Nucleoside

KW - Prmt5

KW - PRMT5 inhibitor

KW - X-ray crystallography

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DO - 10.1016/j.bmc.2022.116820

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JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

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ER -

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

Abstract

Keywords

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