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Abstract
The synthesis of biological active nicotinamide-C-nucleosides has been elaborated. In the context of a structure-activity relationship study the following nucleosides were synthesized: 4-carbamoyl-2-$\beta$-D-ribofuranosylpyridine, 4-carbamoyl-2-(2-deoxy-$\beta$-D-ribofuranosyl)pyridine, 4-carbamoyl-2-(2,3-dideoxy-$\beta$-D-ribofuranosyl)pyridine and 4-carbamoyl-2-(5-deoxy-$\beta$-D-ribofuranosyl)pyridine.
In the first part of this work a convenient pyridine derivative (2-bromo-4-(4,4-dimethyloxazolin-2-yl)pyridine) was synthesized in five steps. The oxazolinyl function appeared to be a good protective group for the carbamoyl function since stirring the oxazoline in CF$\sb3$COOH/H$\sb2$O (4/1) at 50$\sp\circ$C converted this group into the corresponding aminoester. Conversion of 2-bromo-4-(4,4-dimethyloxazolin-2-yl)pyridine into the corresponding pyridyllithium intermediate was established using the following conditions: butyllithium, $-$78$\sp\circ$C, 7 minutes, solvent: THF.
In the second part appropriate protected sugar derivatives had to be synthesized and purified. In the case of the D-ribofuranosyl derivative 2,4;3,5-di-O-benzylidene-aldehydo-D-ribose was synthesized according to the method of Zinner (3 steps). In the case of the 2$\sp\prime$-deoxy-D-ribofuranosyl analogue a new, appropriate protected 2-deoxy-D-ribose derivative had to be synthesized, namely 5-O-tert-butyldiphenylsilyl-2-deoxy-$ 2,3$-O-isopropylidene-aldehydo-D-ribose (4 steps). For the synthesis of the $2\sp\prime,3\sp\prime$-dideoxy-D-ribofuranosyl and the 5$\sp\prime$-deoxy analogue D-ribono-1,4-lactone derivatives were synthesized, respectively 5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-ribono-1,4-lactone (1 step from (S)-4-hydroxymethyl-butyro-1,4-lactone) and 5-deoxy-2,3-isopropylidene-D-ribono-1,4-lactone (4 steps from D-ribono-1,4-lactone). With respect to the next step all sugar derivatives were thoroughly purified.
Coupling of the pyridyllithium intermediate to the sugar derivatives was done in the same conditions, although the reaction time was changed to 7 minutes. After purification the corresponding adducts were obtained in reasonable to good yields. Introduction of a mesyl group in 1$\sp\prime$-position was done by stirring the adduct in pyridine with methanesulphonyl chloride. In the case of the $2\sp\prime,3\sp\prime$-dideoxy- and the 5$\sp\prime$-deoxy derivative this mesyl group was reduced with LiAlH$\sb4$ in dry diethyl ether and the corresponding fully protected nucleosides were obtained. Removal of the protecting groups was done by stirring the mesylates and fully protected nucleosides in CF$\sb3$COOH/H$\sb2$0 (4/1). In the case of the D-ribofuranosyl and 2$\sp\prime$-deoxy-D-ribofuranosyl analogue cyclisation was established during the reaction. The final amide derivatives were obtained by dissolving the corresponding amino esters in methanol and subsequent saturation of this solution with NH$\sb3.$ After heating the reaction mixtures during 7 days at 50$\sp\circ$C gave the amides in good yields.
All compounds were elucidated using $\sp1$H- and $\sp{13}$C-NMR-spectroscopy and DCI-masspectrometry. The anomeric configuration was determined using NMR-spectroscopy. An estimation of the conformational parameters was calculated from the $\sp1$H-NMR coupling constants.
Finally the $\beta$-anomers were evaluated for their cytostatic activity at the REGA-institute (Leuven). A weak cytostatic activity against a number of cell tumor lines was observed in the case of the D-ribofuranosyl- and 5-deoxy-D-ribofuranosyl derivative. All the compounds were also evaluated for their inhibitory effects on the replication of DNA- and RNA-virusses. No appreciable antiviral activity was observed for any of the compounds.
