Abstract
An efficient approach to reversed nucleosides which enables their synthesis in gram quantities is described. N-1′-Pyrimidine reversed nucleosides were prepared by treating of the sodium salt of pyrimidine bases with protected 5-tosyl ribose. Additionally, N-1′, N-3′-disubstituted reversed nucleosides were isolated in the condensation reactions with the 5-halogen pyrimidines. Using the Sonogashira coupling of 5′-iodouracil reversed nucleoside with ethynyltrimethyl silane gave 5′-ethynyl derivative which was further transformed into 5′-acetyl reversed nucleoside. Biological activity of deprotected reversed nucleosides was validated on the panel of six human carcinoma cell lines (HeLa, MIAPaCa2, Hep2, NCI-H358, CaCo-2, and HT-29). 5′-Iodouracil derivative displayed moderate growth inhibition activity against human colon carcinoma (CaCo-2) cells.
Highlights
Modified nucleosides represent a well known class of chemotherapeutic agents for treatment of viral1−4 and cancer5,6 diseases
The synthetic approach to reversed nucleoside analogues is based on the preparation of the already known, suitably protected methyl ribofuranoside 2 (73 %) and its transformation into 5-tosyl derivative 3 (76 %) by adopting the methods described in the literature (Scheme 1)
Following our previously described approach to reversed nucleosides, the sodium salts of the uracil derivatives 4−6 were reacted with ribofuranoside 3 giving the corresponding reversed nucleosides 7, 8 and 10 (Scheme 1)
Summary
Modified nucleosides represent a well known class of chemotherapeutic agents for treatment of viral− and cancer diseases. The practical applicability of nucleoside analogues in chemotherapy largely depends on the stability of the drug in organism, because their catabolism usually includes degradation of nucleosidic linkage. Reversed or iso-nucleosides constitute a class of nucleoside analogues in which the nucleobase is linked to the sugar moiety through a carbon atom other than ribofuranose-C1. This class of compounds appears interesting as drug candidates− due to the lack of glycosidic linkage which makes them more stable to hydrolytic cleavage. The reversed nucleosides represent the largest pool of chiral synthons for the synthesis of aliphatic nucleoside analogues.−
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