Regioselective metalation of 6-methylpurines: synthesis of fluoromethyl purines and related nucleosides for suicide gene therapy of cancer.

Academic Article

Abstract

  • 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.
  • Published In

    Keywords

  • Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Escherichia coli, Genetic Therapy, Halogenation, Humans, Neoplasms, Purine-Nucleoside Phosphorylase, Purines
  • Digital Object Identifier (doi)

    Authorlist

  • Hassan AEA; Parker WB; Allan PW; Secrist JA
  • Start Page

  • 642
  • End Page

  • 656
  • Volume

  • 28
  • Issue

  • 5