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Molecules 2015, 20(9), 15944-15965; doi:10.3390/molecules200915944

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

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
Received: 2 June 2015 / Revised: 22 July 2015 / Accepted: 26 August 2015 / Published: 2 September 2015
(This article belongs to the Section Organic Synthesis)
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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
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Mahajan, T.R.; Ytre-Arne, M.E.; Strøm-Andersen, P.; Dalhus, B.; Gundersen, L.-L. Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1. Molecules 2015, 20, 15944-15965.

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