Collect. Czech. Chem. Commun. 2007, 72, 965-983

Bifunctional Acyclic Nucleoside Phosphonates: 2. Symmetrical 2-{[Bis(phosphono)methoxy]methyl}ethyl Derivatives of Purines and Pyrimidines

Silvie Vrbková*, Martin Dračínský and Antonín Holý

Centre for New Antivirals and Antineoplastics, Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic


Novel bisphosphonate alkylating agent, tetraisopropyl {2-[(mesyloxy)methyl]propane-1,3-diyl}bis(oxymethylene)bisphosphonate 19, was synthesized from diethyl 2,2-bis(hydroxymethyl)malonate. Decarbethoxylation of the diethyl 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate was followed by chloromethylation of 2-[(benzyloxy)methyl]propane-1,3-diol and Arbuzov reaction with triisopropyl phosphite. Bisphosphonate building block 19 was used in the alkylation of various nucleobases (2-amino-6-chloropurine, adenine, 2-amino-6-(cyclopropyl)aminopurine, cytosine, uracil and 4-methoxy-5-methylpyrimidin-2(1H)-one). N9-Substituted purines and N1-substituted pyrimidines were converted to appropriate free bisphosphonic acids. No antiviral or cytostatic activity was detected.

Keywords: Acyclic nucleoside phosphonates; ANPs; Acyclic nucleotide analogues; Phosphonomethyl ethers; Adefovir; Bisphosphonates; Nucleobases.

References: 25 live references.