Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1Report as inadecuate




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1

Department of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, Norway

2

Department of Microbiology, Oslo University Hospital, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway

3

Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway





*

Author to whom correspondence should be addressed.



Academic Editor: Roman Dembinski

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. View Full-Text

Keywords: alkylation; cancer; DNA; enzyme inhibitors; guanine; halogenation alkylation; cancer; DNA; enzyme inhibitors; guanine; halogenation





Author: Tushar R. Mahajan 1, Mari Eknes Ytre-Arne 2,3, Pernille Strøm-Andersen 3, Bjørn Dalhus 2,3 and Lise-Lotte Gundersen 1,*

Source: http://mdpi.com/



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