Trifluoromethylated Nucleosides : A Building Block Approach to Cytotoxic Adenosine Analogues

Abstract

Adenosine analogue nucleosides are a fundamental part of medicinal chemistry. Tubercidin is a well-known example, but its application is limited due to high toxicity. The development of less toxic synthetic analogues is therefore highly desirable. Here we show the synthesis of fluorinated nucleosides based on the pyrrolo[2,3-d]pyrimidine (7-deazapurine) motif. The synthetic approach is based on an easily accessible trifluoromethylated acetoacetate and several amidines, as building blocks. This allows for simultaneous introduction of a CF3 group as well as a variety of C2 substituents for the synthesis of the heterocyclic part, including alkyl, aryl, SMe, Cl, N3 and NH2 moieties. Glycosylation of the fully pre-functionalized heterocycles proceeds with excellent β-selectivity. Cytotoxicities were determined using an AlamarBlue assay with HeLa S3 and Hep G2 cancer cell lines. The effect of C2 substitution was explored and a lead structure candidate with IC50 values of 90 ± 49 nM (HeLa S3) and 28 ± 9 nM (Hep G2) was identified.