Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1
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-oxoguan...
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MDPI AG
2015-09-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/20/9/15944 |
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| author | Tushar R. Mahajan Mari Eknes Ytre-Arne Pernille Strøm-Andersen Bjørn Dalhus Lise-Lotte Gundersen |
| author_facet | Tushar R. Mahajan Mari Eknes Ytre-Arne Pernille Strøm-Andersen Bjørn Dalhus Lise-Lotte Gundersen |
| author_sort | Tushar R. Mahajan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T10:43:41Z |
| format | Article |
| id | doaj.art-275cd6967ec548fbaf0992fad292d919 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-13T10:43:41Z |
| publishDate | 2015-09-01 |
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| series | Molecules |
| spelling | doaj.art-275cd6967ec548fbaf0992fad292d9192022-12-21T23:50:19ZengMDPI AGMolecules1420-30492015-09-01209159441596510.3390/molecules200915944molecules200915944Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1Tushar R. Mahajan0Mari Eknes Ytre-Arne1Pernille Strøm-Andersen2Bjørn Dalhus3Lise-Lotte Gundersen4Department of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, NorwayDepartment of Microbiology, Oslo University Hospital, P. O. Box 4950, Nydalen, N-0424 Oslo, NorwayDepartment of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, P. O. Box 4950, Nydalen, N-0424 Oslo, NorwayDepartment of Microbiology, Oslo University Hospital, P. O. Box 4950, Nydalen, N-0424 Oslo, NorwayDepartment of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, NorwayThe 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.http://www.mdpi.com/1420-3049/20/9/15944alkylationcancerDNAenzyme inhibitorsguaninehalogenation |
| spellingShingle | Tushar R. Mahajan Mari Eknes Ytre-Arne Pernille Strøm-Andersen Bjørn Dalhus Lise-Lotte Gundersen Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1 Molecules alkylation cancer DNA enzyme inhibitors guanine halogenation |
| title | Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1 |
| title_full | Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1 |
| title_fullStr | Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1 |
| title_full_unstemmed | Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1 |
| title_short | Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1 |
| title_sort | synthetic routes to n 9 alkylated 8 oxoguanines weak inhibitors of the human dna glycosylase ogg1 |
| topic | alkylation cancer DNA enzyme inhibitors guanine halogenation |
| url | http://www.mdpi.com/1420-3049/20/9/15944 |
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