Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics.

Maria De Fenza,Daniele D'Alonzo,Anna Esposito,Annalisa Guaragna

doi:10.3390/molecules26061652

Maria De Fenza, Daniele D'Alonzo + Show 2 more

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https://doi.org/10.3390/molecules26061652

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Abstract

The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.

Highlights

The modulation of the activity of carbohydrate processing enzymes represents an important therapeutic target, given the involvement of these proteins in a plethora of metabolic events causing a variety of diverse pathologies [1,2,3]
The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro1,4-dithiin is reported
Polyhydroxylated pyrrolidine scaffolds can be recognized in the structure of Immucillins, which are chemically stable 9-deazapurine C-nucleoside analogues endowed with a variety of therapeutic applications, ranging from the treatment of cancer and autoimmune disorders to parasitic and viral infections [28]

Summary

Introduction

The modulation of the activity of carbohydrate processing enzymes represents an important therapeutic target, given the involvement of these proteins in a plethora of metabolic events causing a variety of diverse pathologies [1,2,3]. Intense efforts have been focused on the identification of inhibitors or enhancers of such enzymes [1,4,5,6,7] with promising therapeutic applications for the treatment of viral infections [8,9], cancer [10], diabetes [11], tuberculosis, lysosomal storage diseases [12], and parasitic protozoa [13]. Polyhydroxylated pyrrolidine scaffolds can be recognized in the structure of Immucillins, which are chemically stable 9-deazapurine C-nucleoside analogues endowed with a variety of therapeutic applications, ranging from the treatment of cancer and autoimmune disorders to parasitic and viral infections [28]. Immucillin-A (1, Imm-A, known as BCX4430 or Galidesivir, Figure 2) has demonstrated to be active in in vivo models against a variety of RNA-dependent RNA polymerases (RdRp)-based pathogens, including Ebola, Marburg, Yellow Fever, and Zika viruses [29,30]

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