Síntese e caracterização de análogos c-nucleosídeos indolizinilicos quaternizados em C-1’

Abstract

C-nucleosides are a class of compounds essential for life. When phosphorylated, they are responsible for processes such as transcription, translation of genetic information, and viral replication. Over the years, they have become the target of research, and several nucleosides have been introduced into clinical practice, with diverse applications, such as antiviral and antitumor agents. The recent COVID-19 pandemic caused by the SARS-CoV-2 virus alerted health agencies to the problems caused by viruses, and antivirals have thus become a major focus of study. Remdesivir was the first C-nucleoside approved by the FDA and the first to be approved for emergency treatment against COVID-19. Remdesivir's structure features a nitrile group at the anomeric carbon, which studies have shown plays a crucial role in interrupting the RNA-dependent RNA polymerase enzyme. Therefore, this work proposes the synthesis of novel C-nucleosides with a quaternized indolizine scaffold at C1'. Six novel C-nucleosides were synthesized in yields ranging from 29 to 78%, based on the construction of the nucleobase with a preformed carbohydrate moiety, which was functionalized by the reaction using perbenzyl riobonolactone. For the syntheses of the desired compounds, pyridinium and quinolinium salts were used for in situ generation of the corresponding ylides, which then reacted with the synthesized alkyne in a 1,3-dipolar reaction. The compounds were characterized by 1D and 2D 1H and 13C NMR and by high-resolution spectrometry, which showed high values for the H-3' hydrogen coupling constant, providing clues about the conformation of the compounds.