Adenine electrophilic reactivity

Acolbifene is also metabolized to a QM (Scheme 10.10)64 formed by oxidation at the C-17 methyl group. This QM is considerably more reactive compared to the tamoxifen quinone methide, which indicates that the acolbifene quinone methide is an electrophile of intermediate stability (Table 10.2). In addition, the acolbifene QM was determined to react with deoxynucleosides, with one of the major adducts resulting from reaction with the exocyclic amino group of adenine.64... 

NAPQI also acts as an electrophile, targeting the mitochondria in particular. This reactive metabolite forms covalent adducts with cellular molecules, particularly proteins with thiol groups. Other targets besides mitochondrial proteins include plasma membrane proteins involved in calcium homeostasis and adenine nucleotides (Dahm and Jones, 1996 Sturgill and Lambert, 1997). 

Imine formation in adenines is presumably a factor of some importance to reactivity towards electrophiles since in A -dialkylated derivatives where imine formation is not possible, further alkylation becomes more difficult. Thus 6-diethylamino-9-methylpurine required prolonged heating with methyl iodide to produce the quaternary salt (92) (65JOC3597) and similarly 6-dimethylamino-9-benzylpurine required 3 days boiling with benzyl bromide in acetonitrile to produce 3,9-dibenzyl-6-dimethylaminopurinium bromide (93) (66JOC2202). Under these circumstances it is clearly difficult to control the alkylation step and quaternization is the normal rule. 

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