Synthesis and cytostatic activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N-6-substituted adenines, 2,6-diaminopurines and related compounds

• Published in: Collection of Czechoslovak chemical communications Vol. 66; no. 10; pp. 1545 - 1592
• Main Authors: Holy, A, Votruba, Tloustova, E, Masojidkova, M
• Format: Journal Article
• Language: English
• Published: PRAGUE 6 Inst Organic Chem And Biochem 01.10.2001
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; cytostatic activity; ANP; HEPATITIS-B-VIRUS; nucleotide analogs; ACYCLIC NUCLEOTIDE ANALOGS; 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE PMEA; HUMAN-IMMUNODEFICIENCY-VIRUS; DNA-POLYMERASES ALPHA; anticancer; antineoplastic; CROSS-COUPLING REACTIONS; MURINE SARCOMA-VIRUS; ADEFOVIR DIPIVOXIL; purines; NUCLEOSIDE PHOSPHONATE ANALOGS; PERIPHERAL-BLOOD LYMPHOCYTES; phosphonates; acyclic nucleoside phosphonates
• ISSN: 0010-0765; 1212-6950
• DOI: 10.1135/cccc20011545

N-6-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-(diisopropoxyphosphoryl)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 N-6-substituted purifies 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 seas analogously converted to N-6-substituted 2,6-diamino-9-[2-(2-phosphonoethoxy)ethyl]purines 151-153. Alkylation of N-6-substituted 2,6-diamino-purines 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 N-6-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.