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Inactivation of O-alkylguanine-DNA alkyltransferase. 1. Novel O- (hetarylmethyl)guanines having basic rings in the side chain

Journal of Medicinal Chemistry, ISSN: 0022-2623, Vol: 41, Issue: 26, Page: 5265-5271
1998
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Article Description

A number of novel guanine derivatives containing heterocyclic moieties at the O-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O-substituents were investigated in which the benzene ring of the known agent, O- benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O- benzylguanine. The present paper focuses on O-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O- substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12),5-bromothenyl (17), and 2-chloro-4- picolyl (21) derivatives.

Bibliographic Details

R. Stanley McElhinney; Dorothy J. Donnelly; Joan E. McCormick; T. Brian H. McMurry; Jane Kelly; Amanda J. Watson; Joseph A. Rafferty; Rhoderick H. Elder; Mark R. Middleton; Mark A. Willington; Geoffrey P. Margison

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

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