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

Abstract

Abstract:The human 8-oxoguanine DNA glycosylase OGG1 is involved in 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 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.

Inhibitors of DNA Glycosylases as Prospective Drugs

“…Inhibitors of OGG1 have been reported in the literature but have not yet reached clinical trials. Mechanism-based approaches had only limited success: both oxoG base and its analogs proved to be weak inhibitors [182,183], while substituted 2,6-diaminopurines performed slightly better [76]. Experimental and computational screening of small-molecule pharmacological libraries produced several hits that were expanded into inhibitors with submicromolar affinity, structurally unrelated to the OGG1 substrate [72][73][74] (Table 2).…”