SYNTHESIS AND BIOLOGICAL EFFECTS OF 9-(3-HYDROXY-2-PHOSPHONOMETHOXYPROPYL) DERIVATIVES OF DEAZAPURINE BASES

Analogs of antiviral 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine (HPMPA, I), containing modified purine bases 3-deazaadenine XII, 1-deazaadenine XIV, 7-deaza-7-cyanoadenine XXXII and 3-deazaguanine XXXVIII. were prepared by alkylation of the bases with synthon XVII, containing preformed structure of the side chain, in the presence of cesium carbonate. The obtained protected derivatives were deblocked successively with sodium methoxide and bromotrimethylsilane to give phosphonic acids XII, XIV. XXXII and XXXVIII. Compounds XII, XIV and XVI were also prepared from (S)- or (R)-9-(2,3-dihydroxypropyl) derivatives VI, VII and XV by reaction with chloromethanephosphonyl dichloride, isomerization of the arising 2'- and 3'-chloromethanephosphonates and conversion of the 3'-isomers into the phosphonic acids in alkaline medium. The 3-deaza analog XII was also prepared by ditritylation of VI, reaction with bis(2-propyl) tosyloxymethanephosphonate (XXII), subsequent acid hydrolysis and reaction with bromotrimethylsilane. 3-DeazaHPMPA (XII) is a potent inhibitor of DNA viruses (HSV-1, HSV-2, VZV, CMV) and exhibits activity against Plasmodium sp.