Cytotoxicity reduction by O-nicotinoylation of antiviral 6-benzylaminopurine ribonucleosides. (August 2022)

• Record Type: Journal Article
• Authors: Zenchenko, Anastasia A.; Oslovsky, Vladimir E.; Varizhuk, Irina V.; Karpova, Evgenia V.; Osolodkin, Dmitry I.; Kozlovskaya, Liubov I.; Ishmukhametov, Aydar A.; Drenichev, Mikhail S.
• Is Part Of: Toxicology in vitro. Volume 82(2022)
• Publication Date: 2022-08
• Subjects: 6-Benzylaminopurine ribonucleosides -- O-Nicotinoylation -- Biodegradable lipophilic groups -- Cytotoxicity reduction -- Antiviral activity -- Enterovirus EV-A71; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2022.105355
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: One of the promising approaches in the development of nucleoside prodrugs is to use the nucleoside analogs containing lipophilic biodegradable residues, which are cleaved to biologically active forms after metabolic transformations in the cell. The introduction of such fragments makes it possible to reduce the general toxicity of the drug candidate and increase its stability in the cell. In order to study the influence of biodegradable lipophilic groups on antiviral activity and cytotoxicity, in this work we synthesized N 6 -benzyl-2′, 3′, 5′-tri- O -nicotinoyl adenosine and N 6 -(3-fluorobenzyl)-2′, 3′, 5′-tri- O -nicotinoyl adenosine, derivatives of N 6 -benzyladenosine (BAR) and N 6 -(3-fluorobenzyl)adenosine (FBAR), which had previously shown prominent antiviral activity against human enterovirus EV-A71 but appeared to be cytotoxic. The obtained fully- O -nicotinoylated BAR and FBAR inhibited reproduction of EV-A71 strains BrCr and 46973 and manifested significantly lower cytotoxicity compared to non-protected compounds. In addition, we performed enzymatic hydrolysis of the fully- O -nicotinoylated FBAR in the presence of esterases (CalB and PLE) to investigate metabolic degradation of O -nicotinoylated compounds in cells. Both enzymes hydrolyzed the tested substrate to form the corresponding O -deprotected nucleoside that may suggest the role of hydrolase-type enzymes as general participants of metabolic activation of O -nicotinoylated prodrugs in different cells. Graphical abstract: Unlabelled Image Highlights: 6-Benzylaminopurine ribonucleosides with biodegradable O- nicotinoyl ester moieties. Fully- O -nicotinoylated nucleosides exhibit decrease in cytotoxicity in RD cells. Fully- O -nicotinoylated nucleosides manifest antiviral activity against EV-A71. Gradual hydrolysis of fully- O -nicotinoylated nucleosides in the presence of esterases.