Trifluoromethylated Nucleosides: A Building Block Approach to Cytotoxic Adenosine Analogues
Authors:
- 20 August 2014
- journal article
- research article
- Published by Wiley in European Journal of Organic Chemistry
- Vol. 2014 (28) , 6314-6320
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.Keywords
This publication has 30 references indexed in Scilit:
- Synthesis of a 6-Methyl-7-deaza Analogue of Adenosine That Potently Inhibits Replication of Polio and Dengue VirusesJournal of Medicinal Chemistry, 2010
- Synthesis of Fluorinated Pyrrolo[2,3-b]pyridine and Pyrrolo[2,3-d]pyrimidine NucleosidesSynthesis, 2009
- Facile Synthesis of Fluorinated Pyrrolo[2,3-b]pyridinesSynlett, 2009
- Fluorinated nucleosides: Synthesis and biological implicationJournal of Fluorine Chemistry, 2008
- Fluorine in Pharmaceuticals: Looking Beyond IntuitionScience, 2007
- Synthesis of 1, 7-Dideazapurine Ribonucleosides and DeoxyribonucleosidesNucleosides and Nucleotides, 1993
- 9-Deazapurine nucleosides. The synthesis of certainN-5-β-d-ribofuranosylpyrrolo[3,2-d]pyrimidinesJournal of Heterocyclic Chemistry, 1990
- Methods generale d'acess aux trifluoromethylcetones. 1ère partie: Alkylation directe du trifluoroacetylacetate d'ethyleJournal of Fluorine Chemistry, 1989
- Inhibition of metabolic cooperation by phorbol esters in a cell culture system based on adenosine kinase deficient mutants of V79 cellsCarcinogenesis, 1985
- THE STRUCTURE OF NUCLEOSIDES IN RELATION TO THEIR BIOLOGICAL AND BIOCHEMICAL ACTIVITY: A SUMMARYAnnals of the New York Academy of Sciences, 1975