Collect. Czech. Chem. Commun. 2001, 66, 1545-1592

Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds

Antonín Holý*, Ivan Votruba, Eva Tloušťová and Milena Masojídková

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic


N6-Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)- ethyl] (PME), 9-[(R)-2-(phosphonomethoxy)propyl] [(R)-PMP] and enantiomeric (S)-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (26-28) or 2-amino-6-chloro-9-{[2-(diisopropoxy- phosphoryl)methoxy]alkyl}purines (29-31) followed by treatment of the diester intermediates 32 with bromo(trimethyl)silane and hydrolysis. Diesters 32 were also obtained by reaction of N6-substituted purines with synthons 23-25 bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine (9) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate (148) gave the diester 149 which was analogously converted to N6-substituted 2,6-diamino- 9-[2-(2-phosphonoethoxy)ethyl]purines 151-153. Alkylation of N6-substituted 2,6-diaminopurines with (R)-[(trityloxy)methyl]oxirane (155) followed by reaction of thus-obtained intermediates 156 with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate (158) followed by deprotection of the intermediates 159 gave N6-substituted 2,6-diamino-9-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]purines 160-163. The highest cytostatic activity in vitro was exhibited by the following N6-derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl (53), allyl (54), [(2-dimethylamino)ethyl] (68), cyclopropyl (75) and dimethyl (91). In CCRF-CEM cells, the cyclopropyl derivative 75 is deaminated to the guanine derivative PMEG (3) which is then converted to its diphosphate.

Keywords: Purines; Nucleotide analogs; Phosphonates; Acyclic nucleoside phosphonates; ANP; Cytostatic activity; Antineoplastic; Anticancer.

References: 108 live references.