Synthesis of Novel Thiopurine Pyranonucleosides: Evaluation of Their Bioactivity

Abstract

We report the synthesis of novel thiopurine pyranonucleosides. Direct coupling of silylated 6-mercaptopurine and 6-thioguanine with the appropriate pyranoses 1a-e via Vorbrüggen nucleosidation, gave the N-9 linked mercaptopurine 2a-e and thioguanine 4a-e nucleosides, while their N-7 substituted congeners 10a-e and 7a-e, were obtained through condensation of the same acetates with 6-chloro and 2-amino-6-chloropurines, followed by subsequent thionation. Nucleosides 3a-e, 5a-e, 8a-e, and 11a-e were evaluated for their cytostatic activity in three different tumor cell proliferative assays.

Study of the N7 Regioselective Glycosylation of 6-Chloropurine and 2,6-Dichloropurine with Tin and Titanium Tetrachloride

“…In the most promising report in the literature, peracetylated 6-chloro-7-(β-Dglucopyranosyl)purine (3a) was isolated in 60% yield by the modified Vorbruggen method. 50 However, we found that the NMR data they reported for the prepared compound corresponded to N 9 -isomer 4a and thus were consistent with the spectra of the N 9 -isomer in other reports where the NMR spectra of both isomers were provided. 18,30,33 Additionally, analogous N 7 -galactosyl 3d and mannosyl 3e derivatives were incorrectly described in this paper, which was verified experimentally in our work.…”

“…An approximately equimolar ratio of N 7 /N 9 -isomers and a low conversion were observed several times during the reproduction of a similar procedure described in another publication (Table 1, entry 15). 50 Similar results in terms of isomer distribution were observed using SnCl 4 or TiCl 4 . An approximately equimolar ratio of both isomers was attained after 22 h at room temperature (Table 1, entries 16 and 19), and over time, the ratio changed to favor the N 9 -isomer 4a (Table 1, entries 17 and 20).…”

“… a Based on high-performance liquid chromatography (HPLC) analysis. b Method described for the 4a isomer c Isolated yields of 3a (70%) and 4a (20%). d Isolated yield of 3a (60%). e Observed results based on the conditions reported by Komiotis f Isolated yields of 3g (25%) and 4g (20%). …”

“…Optimization of Glucosylation Reactions of 6-Chloropurine (1) Isolated yield of 3a (60%). e Observed results based on the conditions reported by Komiotis 50. f Isolated yields of 3g (25%) and 4g (20%).…”

Synthesis of [15N4] purine labeled cytokinin glycosides derived from zeatins and topolins with 9‐β‐d, 7‐β‐d‐glucopyranosyl, or 9‐β‐d‐ribofuranosyl group

“…To date, three methods have been described. The most promising method, where peracetylated 6‐chloropurine‐7‐β‐ d ‐glucopyranoside was isolated in 60% yield, was reported in a literature . We repeated this procedure with unlabeled 1 and found that authors prepared 9‐isomer 2 instead of 7‐isomer 3 .…”