Synthesis, Antiviral and Cytostatic Evaluation of Unsaturated Exomethylene and Keto D-Lyxopyranonucleoside Analogues

Niki Tzioumaki 1, Evangelia Tsoukala 1, Stella Manta 1, George Agelis 2, Jan Balzarini 3, Dimitri Komiotis *

^*Correspondence to Dimitri Komiotis, ¹Department of Biochemistry and Biotechnology, Laboratory of Organic Chemistry, University of Thessaly, Larissa, Greece. Fax: +30 2410 565-290

Funded by:
Geconcerteerde Onderzoeksacties of the Katholieke Universtiteit Leuven; Grant Number: GOA no. 05/19

Keywords

Cytotoxicity • Exomethylene nucleosides • Ketonucleosides • Unsaturated nucleosides

Abstract

This report describes the synthesis of unsaturated exomethylene lyxopyranonucleoside analogues as potential biologically active agents. Commercially available 1,2,3,4-tetra-O-acetyl--D-lyxopyranose 1 was condensed with silylated thymine and uracil, respectively, deacetylated and acetalated to afford 1-(2,3-O-isopropylidene--D-lyxopyranosyl)thymine 4a and 1-(2,3-O-isopropylidene--D-lyxopyranosyl)uracil 4b. The new derivatives 1-(2,3,4-trideoxy-4-methylene--pent-2-enopyranosyl)thymine 8a and 1-(2,3,4-trideoxy-4-methylene--pent-2-enopyranosyl)uracil 8b were prepared via two different key intermediates, 7a, b and 13a, b in order to elucidate the influence of 2,3-unsaturation and to clarify the difference between the keto and exomethylene group on the biological activity of the target molecules. Compounds 7a, b, 8a, b, and 13a, b were evaluated for their antiviral and cytostatic activity using several virus strains and cell lines. Whereas no marked antiviral activity was noticed, 13a and 13b showed a cytostatic activity that ranged between 7 and 23 M for 13a and 26 and 38 M for 13b against murine leukemia L1210, human lymphocyte Molt4/C8 and CEM cells, and human breast carcinoma MCF7 cells.