title: Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1.
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.
authors.affiliation: Department of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, Norway. t.r.mahajan@kjemi.uio.no.
authors.forename: Tushar R
authors.initials: TR
authors.lastname: Mahajan
authors.affiliation: Department of Microbiology, Oslo University Hospital, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway. pernille.strom-andersen@medisin.uio.no.|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.
authors.forename: Mari Eknes
authors.initials: ME
authors.lastname: Ytre-Arne
authors.affiliation: 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.
authors.forename: Pernille
authors.initials: P
authors.lastname: Strøm-Andersen
authors.affiliation: Department of Microbiology, Oslo University Hospital, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway. pernille.strom-andersen@medisin.uio.no.|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.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Dalhus
authors.affiliation: Department of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, Norway. l.l.gundersen@kjemi.uio.no.
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Gundersen
mesh_terms: D000478:Alkylation; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
keywords: DNA; alkylation; cancer; enzyme inhibitors; guanine; halogenation