Synthesis and Investigation of the Antitumor Properties of Novel, Bicyclic Furopyrimidine, Pyrrolopyrimidine and Pyrimidopyridazine Nucleoside Analogues

Abstract

A series of nine hitherto unknown bicyclic pyrimidine nucleoside analogues (BCNAs) bearing bicyclic furo[2,3-d]pyrimidin-2(3H)-one, 3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one and 5,6-dihydropyrimido[4,5-c]pyridazin-7(8H)-one bases were prepared in a straightforward approach. Each of the synthesized compounds possesses a β-d-ribofuranose, β-d-2-deoxyribofuranose or β-d-arabinofuranose moiety attached to the heterocyclic ring system. This is one of few examples of the synthesis of pyrrolo[2,3-d]pyrimidin-2(7H)-one and dihydropyrimido[4,5-c]pyridazin-7(8H)-one nucleosides, and the first example of such nucleosides possessing an arabinose moiety. A key synthetic step involved a Sonogashira coupling reaction. For the coupling with 4-phenyl-1-butyne, deprotected 5-iodouridine, 5-iodo-2′-deoxyuridine and 5-iodoarabinouridine were used, and this reaction was followed by cycloisomerization and subsequent conversion of the furan ring into a pyrrole or a pyridazine ring. This approach resulted in the creation of a small library of compounds, which were evaluated for their antiproliferative properties against HL-60 and Jurkat E6.1 cell lines. Of all tested compounds, only 6-(2-phenylethyl)-3-(β-d-ribofuranosyl)furo[2,3-d]pyrimidin-2(3H)-one exhibited weak antiproliferative activity, with IC₅₀ values of 54 and 81 μM for HL-60 and Jurkat E6.1 cells, respectively.

Key words

bicyclic pyrimidine nucleoside analogues (BCNAs) - cytarabine analogues - cytotoxicity - Sonogashira reaction - cycloisomerization - furopyrimidine nucleosides - pyrrolopyrimidine nucleosides - pyrimidopyridazine nucleosides

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