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Trifluoromethylated Nucleosides: A Building Block Approach to Cytotoxic Adenosine Analogues
Author(s) -
Drexler Johannes,
Groth Ulrich
Publication year - 2014
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201402755
Subject(s) - chemistry , hela , pyrimidine , combinatorial chemistry , stereochemistry , aryl , cancer cell lines , glycosylation , alkyl , cancer cell , organic chemistry , cell , biochemistry , cancer , medicine
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 CF 3 group as well as a variety of C2 substituents for the synthesis of the heterocyclic part, including alkyl, aryl, SMe, Cl, N 3 and NH 2 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 IC 50 values of 90 ± 49 nM (HeLa S3) and 28 ± 9 nM (Hep G2) was identified.