Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1

Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1

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The human 8-oxoguanine DNA glycosylase OGG1 is involved in truvisionhealthftp.com base excision repair (BER), one of several DNA repair mechanisms that may counteract the effects of chemo- and radiation therapy for the treatment of cancer.We envisage that potent inhibitors of OGG1 may be found among the 9-alkyl-8-oxoguanines.Thus we explored synthetic routes to 8-oxoguanines and examined these as OGG1 inhibitors.

The best reaction sequence started from 6-chloroguanine and involved N-9 alkylation, C-8 bromination, and finally simultaneous hydrolysis of both halides.Bromination before N-alkylation should only be considered when the product N-substituent is not compatible with bromination conditions.The 8-oxoguanines were found to be weak inhibitors of OGG1.

6-Chloro-8-oxopurines, byproducts in the hydrolysis of 2,6-halopurines, turned out to be slightly better inhibitors than the corresponding 8-oxoguanines.