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

Tushar R Mahajan; Mari Eknes Ytre-Arne; Pernille Strøm-Andersen; Bjørn Dalhus; Lise-Lotte Gundersen

doi:10.3390/molecules200915944

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

Molecules. 2015 Sep 2;20(9):15944-65. doi: 10.3390/molecules200915944.

Authors

Tushar R Mahajan¹, Mari Eknes Ytre-Arne^{2

3}, Pernille Strøm-Andersen³, Bjørn Dalhus^{2

3}, Lise-Lotte Gundersen⁴

Affiliations

¹ Department of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, Norway. t.r.mahajan@kjemi.uio.no.
² Department of Microbiology, Oslo University Hospital, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway. pernille.strom-andersen@medisin.uio.no.
³ Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway. pernille.strom-andersen@medisin.uio.no.
⁴ Department of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, Norway. l.l.gundersen@kjemi.uio.no.

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkylation
DNA Glycosylases / antagonists & inhibitors
DNA Glycosylases / metabolism*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Guanine / analogs & derivatives*
Guanine / chemical synthesis
Guanine / chemistry
Guanine / pharmacology
Humans
Substrate Specificity

Substances

Enzyme Inhibitors
8-hydroxyguanine
Guanine
DNA Glycosylases
oxoguanine glycosylase 1, human