Collect. Czech. Chem. Commun. 2011, 76, 1103-1119
Published online 2011-08-24 09:19:26

2-Thiozebularine: base modified nucleoside fully constrained in C3′-endo conformation in solution

Katarzyna Ebenrytera, Stefan Jankowskia, Janina Karolak-Wojciechowskab, Andrzej Fruzińskib, Julia Kaźmierczak-Baranskac, Barbara Nawrotc and Elzbieta Sochackaa,*

a Institute of Organic Chemistry, Technical University of Lodz, Zeromskiego 116, 90-924 Lodz, Poland
b Institute of General and Ecological Chemistry, Technical University of Lodz, Zeromskiego 116, 90-924 Lodz, Poland
c Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies of the Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland


2-Thiopyrimidinone ribofuranoside (2-thiozebularine, s2zeb) was synthesized by the adaptation of silyl method of N-glycosidic bond formation and using thionation of protected 2-oxonucleoside derivative (zebularine, zeb) with Lawesson reagent. The X-ray crystal structure of s2zeb and NMR determined conformations of s2zeb and zeb in solution were compared with structures of 2-thiouridine (s2U) and uridine (U). In the solid state s2zeb molecule adopts conformation typical for ribonucleosides: C3′-endo C2′-exo twist type of ribofuranose pucker, anti of N-glycosidic bond and trans around C4′–C5′ bond. In aqueous solution, however, almost 100% population of s2zeb exhibits C3′-endo ribofuranose pucker. The population of N-conformer of s2zeb is about 20% higher than for zeb (analogously to pair of s2U and U nucleosides) indicating similar influence of steric effect of bulky sulfur atom on stabilization of N-type ribose conformation. Interestingly, the absence of 4-carbonyl function in zeb and s2zeb raises the population of C3′-endo conformation by about 30% in comparison to U and s2U as a result of significant anomeric effect. Additive action of both effects makes the 2-thiozebularine almost fully constrained in C3′-endo conformation in aqueous solution. Cytotoxic properties of s2zeb are less pronounced in comparison to zebularine, with IC50 > 100 mM for HeLa and K562 cancer cells and for HUVEC non-cancerous cells.

Keywords: 2-Thiozebularine; Zebularine; Modified nucleosides; Conformation of nucleosides; X-ray; NMR; Cytotoxity of nucleosides.

References: 39 live references.