Synthesis of O2- and N3-(2-Phosphonomethoxy)ethyl Derivatives of 6-Phenyl- and 6-Pyridinyl-5-azacytosine

Abstract

A series of hydrolytically stable Oand N-(2-phosphonomethoxy)ethyl (PME) derivatives of 6-phenyl, pyridin-2, -3 and -4-yl-5-azacytosines was prepared by their alkylation with diisopropyl (2-chloroethoxy)methylphosphonate followed by the deprotection. No antitumor or antiviral activity was found except for 6-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine (13d) which exhibited slight activity against feline herpesvirus in CrFK cell cultures with IC50 = 6.7 μg/mL. INTRODUCTION 5-Azacytosine nucleosides are well-known anticancer agents with an epigenetic mechanism of action. Two of them, 2’-deoxy-5-azacytidine (decitabine, Dacogen, 1; its alpha anomer 2 shows comparable epigenetic activity but with much lower toxicity) and 5-azacytidine(Vidaza, 3), were approved for treatment of myelodisplastic syndromes (MDS, Figure 1). Others, i.e. 5-azacytosine arabinoside (fazarabine, 4) and 5,6-dihydro-5-azacytidine (5), are being investigated in clinical trials. On the other hand, 2’-deoxy-5,6-dihydro-5-azacytidine (6) exhibits a very strong anti-HIV potency, which enables, especially when its prodrug KP-1461 (7) is applied, the eradication of HIV from laboratory cell cultures. Compound 6 does not inhibit reverse transcription like other nucleosides or acyclic nucleoside phosphonates, but, after incorporation into proviral DNA, it acts as an ambiguous base, which causes mutations. An accumulation of the errors throughout the viral genome during the replication cycle may lead to a progressive decrease of the fitness of the virus and further to a lethal mutagenesis, which may cause a total collapse of the virus population. Recently, a pronounced antiviral activity has been HETEROCYCLES, Vol. 83, No. 4, 2011 797