Innovative Strategies for the Construction of Diverse 1′-Modified C-Nucleoside Derivatives

Subhankar Panda; Tej Narayan Poudel; Pooja Hegde; Courtney C. Aldrich

doi:10.1021/acs.joc.1c01920

Innovative Strategies for the Construction of Diverse 1′-Modified C-Nucleoside Derivatives

Subhankar Panda, Tej Narayan Poudel, Pooja Hegde, Courtney C. Aldrich

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

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Abstract

Modified C-nucleosides have proven to be enormously successful as chemical probes to understand fundamental biological processes and as small-molecule drugs for cancer and infectious diseases. Historically, the modification of the glycosyl unit has focused on the 2′-, 3′-, and 4′-positions as well as the ribofuranosyl ring oxygen. By contrast, the 1′-position has rarely been studied due to the labile nature of the anomeric position. However, the improved chemical stability of C-nucleosides allows the modification of the 1′-position with substituents not found in conventional N-nucleosides. Herein, we disclose new chemistry for the installation of diverse substituents at the 1′-position of C-nucleosides, including alkyl, alkenyl, difluoromethyl, and fluoromethyl substituents, using the 4-amino-7-(1′-hydroxy-d-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine scaffold as a representative purine nucleoside mimetic.

Original language	English (US)
Pages (from-to)	16625-16640
Number of pages	16
Journal	Journal of Organic Chemistry
Volume	86
Issue number	23
DOIs	https://doi.org/10.1021/acs.joc.1c01920
State	Published - Dec 3 2021

Bibliographical note

Funding Information:
This research was supported by a grant from the NIH (AI136445) to C.C.A. We would like to thank Dr. Victor G. Young, Jr. from the Department of Chemistry, University of Minnesota for X-ray crystallographic analysis. We would also like to thank collaborators from Waters Corporation (including Marguerite Arechederra, Matthew Lauber, and Erica Manandhar) for their donation of HPLC columns in support of this project.

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abstract = "Modified C-nucleosides have proven to be enormously successful as chemical probes to understand fundamental biological processes and as small-molecule drugs for cancer and infectious diseases. Historically, the modification of the glycosyl unit has focused on the 2′-, 3′-, and 4′-positions as well as the ribofuranosyl ring oxygen. By contrast, the 1′-position has rarely been studied due to the labile nature of the anomeric position. However, the improved chemical stability of C-nucleosides allows the modification of the 1′-position with substituents not found in conventional N-nucleosides. Herein, we disclose new chemistry for the installation of diverse substituents at the 1′-position of C-nucleosides, including alkyl, alkenyl, difluoromethyl, and fluoromethyl substituents, using the 4-amino-7-(1′-hydroxy-d-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine scaffold as a representative purine nucleoside mimetic.",

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N2 - Modified C-nucleosides have proven to be enormously successful as chemical probes to understand fundamental biological processes and as small-molecule drugs for cancer and infectious diseases. Historically, the modification of the glycosyl unit has focused on the 2′-, 3′-, and 4′-positions as well as the ribofuranosyl ring oxygen. By contrast, the 1′-position has rarely been studied due to the labile nature of the anomeric position. However, the improved chemical stability of C-nucleosides allows the modification of the 1′-position with substituents not found in conventional N-nucleosides. Herein, we disclose new chemistry for the installation of diverse substituents at the 1′-position of C-nucleosides, including alkyl, alkenyl, difluoromethyl, and fluoromethyl substituents, using the 4-amino-7-(1′-hydroxy-d-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine scaffold as a representative purine nucleoside mimetic.

AB - Modified C-nucleosides have proven to be enormously successful as chemical probes to understand fundamental biological processes and as small-molecule drugs for cancer and infectious diseases. Historically, the modification of the glycosyl unit has focused on the 2′-, 3′-, and 4′-positions as well as the ribofuranosyl ring oxygen. By contrast, the 1′-position has rarely been studied due to the labile nature of the anomeric position. However, the improved chemical stability of C-nucleosides allows the modification of the 1′-position with substituents not found in conventional N-nucleosides. Herein, we disclose new chemistry for the installation of diverse substituents at the 1′-position of C-nucleosides, including alkyl, alkenyl, difluoromethyl, and fluoromethyl substituents, using the 4-amino-7-(1′-hydroxy-d-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine scaffold as a representative purine nucleoside mimetic.

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Innovative Strategies for the Construction of Diverse 1′-Modified C-Nucleoside Derivatives

Abstract

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