Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain.

2.50
Hdl Handle:
http://hdl.handle.net/10541/92914
Title:
Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain.
Authors:
McElhinney, R S; Donnelly, Dorothy J; McCormick, J E; Kelly, Jane; Watson, Amanda J; Rafferty, Joseph A; Elder, Rhoderick H; Middleton, Mark R; Willington, Mark; McMurry, T Brian H; Margison, Geoffrey P
Abstract:
A number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-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 O6-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.
Affiliation:
University Chemical Laboratory, Trinity College, Dublin 2, Ireland.
Citation:
Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain. 1998, 41 (26):5265-71 J. Med. Chem.
Journal:
Journal of Medicinal Chemistry
Issue Date:
17-Dec-1998
URI:
http://hdl.handle.net/10541/92914
DOI:
10.1021/jm9708644
PubMed ID:
9857094
Type:
Article
Language:
en
ISSN:
0022-2623
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMcElhinney, R Sen
dc.contributor.authorDonnelly, Dorothy Jen
dc.contributor.authorMcCormick, J Een
dc.contributor.authorKelly, Janeen
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorRafferty, Joseph Aen
dc.contributor.authorElder, Rhoderick Hen
dc.contributor.authorMiddleton, Mark Ren
dc.contributor.authorWillington, Marken
dc.contributor.authorMcMurry, T Brian Hen
dc.contributor.authorMargison, Geoffrey Pen
dc.date.accessioned2010-02-24T13:13:15Z-
dc.date.available2010-02-24T13:13:15Z-
dc.date.issued1998-12-17-
dc.identifier.citationInactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain. 1998, 41 (26):5265-71 J. Med. Chem.en
dc.identifier.issn0022-2623-
dc.identifier.pmid9857094-
dc.identifier.doi10.1021/jm9708644-
dc.identifier.urihttp://hdl.handle.net/10541/92914-
dc.description.abstractA number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-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 O6-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.en
dc.language.isoenen
dc.subjectCultured Tumour Cellsen
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshRecombinant Proteins-
dc.subject.meshTumor Cells, Cultured-
dc.titleInactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain.en
dc.typeArticleen
dc.contributor.departmentUniversity Chemical Laboratory, Trinity College, Dublin 2, Ireland.en
dc.identifier.journalJournal of Medicinal Chemistryen

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