Regioselective Metalation of 6-Methylpurines: Synthesis of Fluoromethyl Purines and Related Nucleosides for Suicide Gene Therapy of Cancer

Autor:	John A. Secrist, William B. Parker, Abdalla E. A. Hassan, Paula W. Allan
Rok vydání:	2009
Předmět:	Purine Halogenation Stereochemistry Metalation Purine nucleoside phosphorylase Antineoplastic Agents Genetic Therapy General Medicine Prodrug Riboside Biochemistry chemistry.chemical_compound Purine-Nucleoside Phosphorylase chemistry Purines Cell Line Tumor Neoplasms Escherichia coli Genetics Humans Molecular Medicine Moiety Purine metabolism Nucleoside Cell Proliferation
Zdroj:	Nucleosides, Nucleotides & Nucleic Acids. 28:642-656
ISSN:	1532-2335 1525-7770
DOI:	10.1080/15257770903091938
Popis:	Metalation of 6-methyl-9-(tetrahydro-2H-pyran-2-yl)purine (10) with lithiating agents of varying basicities such as n-BuLi and LiHMDS in THF at -78 degrees C resulted in metalation at both of the 6-CH(3) moiety and the 8-CH position, irrespective of the molar equivalence of the base. On the other hand, a regioselective metalation at the 6-CH(3) moiety of 10 was observed with NaHMDS or KHMDS, under similar conditions. Treatment of the potassium salts of 10 and of the protected riboside derivative 6-methyl-9-(beta-D-2,3,5-tri-O-tert-butyldimethylsilylribofuranosyl)purine (22) with N-fluorobenzenesulfonamide (NFSI) at -78 degrees C gave the corresponding 6-fluoromethylpurine derivatives 11 and 23, respectively, in good yields. Deprotection of 11 and 23 under standard conditions gave 6-fluoromethylpurine (6-FMeP, 3) and 6-fluoromethyl-9-(beta-D-ribofuranosyl)purine (6-FMePR, 4), respectively, in high yield. Both 3 and 4 demonstrated cytotoxic activity against CCRF-CEM cells in culture. 6-FMePR is a good substrate for E. coli purine nucleoside phosphorylase (E. coli PNP) with a comparable substrate activity to that of the parent nucleoside, 6-methyl-9-(beta-D-ribofuranosyl)purine (6-MePR, 21). The cytotoxic activity of 6-FMeP along with the substrate activity of 6-FMePR with E. coli PNP meet the fundamental requirements for using 6-FMeP as a potential toxin in PNP/prodrug based cancer gene therapy.
Databáze:	OpenAIRE
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