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

Molecules

Tushar R. Mahajan³  Mari Eknes Ytre-Arne²  Pernille Strøm-Andersen¹  Bjørn Dalhus²  Lise-Lotte Gundersen³ 

[1] Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway; E-Mail:;Department of Microbiology, Oslo University Hospital, P. O. Box 4950, Nydalen, N-0424 Oslo, Norway; E-Mails:;Department of Chemistry, University of Oslo, P. O. Box 1033, Blindern, N-0315 Oslo, Norway; E-Mail:

关键词: alkylation;    cancer;    DNA;    enzyme inhibitors;    guanine;    halogenation;   

DOI  :  10.3390/molecules200915944

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.