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Abstract
Syntheses of α-branched alkyl and aryl substituted 9-[2-(phosphonomethoxy)ethyl]purines from substituted 1,3-dioxolanes have been developed. Key synthetic precursors, α-substituted dialkyl [(2-hydroxyethoxy)methyl]phosphonates were prepared via Lewis acid mediated cleavage of 1,3-dioxolanes followed by reaction with dialkyl or trialkyl phosphites. The best preparative yields were achieved under conditions utilizing tin tetrachloride as Lewis acid and triisopropyl phosphite. Attachment of purine bases to dialkyl [(2-hydroxyethoxy)methyl]phosphonates was performed by Mitsunobu reaction. Final α-branched 9-[2-(phosphonomethoxy)ethyl]purines were tested for antiviral, cytostatic and antiparasitic activity, the latter one determined as inhibitory activity towards Plasmodium falciparum enzyme hypoxanthine-guanine-xanthine phosphoribosyltransfesase. In most cases biological activity was only marginal.
Acknowledgements
This work was supported by the Subvention for development of research organization RVO 61388963 and the grant 14–00522S by the Grant Agency of the Czech Republic. The authors´ thanks are due to Professor Luke Guddat and his team (University of Queensland, Australia) for HGXPRT inhibitory assays, Dr P. Fiedler from this Institute for measurement of IR spectra, the staff of the mass spectrometry (Dr J. Cvačka, Head), analytical departments of the Institute (Dr S. Matějková, Head), and Mrs. Leentje Persoons, Mrs. Lies Van Den Heurck, Mrs. Ellen De Waegenaere and Mrs. Lizette van Berckelaer for biological assays.