Substituted O6-Benzylguanine Derivatives and Their Inactivation of Human O6-Alkylguanine-DNA Alkyltransferase

• Published in: Journal of medicinal chemistry Vol. 37; no. 3; pp. 342 - 347
• Main Authors: Chae, Mi Young, McDougall, Mark G, Dolan, M. Eileen, Swenn, Kristin, Pegg, Anthony E, Moschel, Robert C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-02-1994
• Subjects: Antineoplastic agents; Biological and medical sciences; Colonic Neoplasms - enzymology; General aspects; Guanine - analogs & derivatives; Guanine - chemistry; Humans; Medical sciences; Methyltransferases - antagonists & inhibitors; Molecular Structure; O-Methylguanine-DNA Methyltransferase; Pharmacology. Drug treatments; Structure-Activity Relationship; Tumor Cells, Cultured; Methylated-DNA-protein-cysteine S-methyltransferase; Purine nucleoside; Methyltransferases; Structure activity relation; Enzyme; Transferases; DNA; Enzyme inhibitor; Inhibition; Repair; Chemical synthesis; Molecular adduct
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00029a005

Several new O6-benzylguanine analogs bearing increasingly bulky substituent groups on the benzene ring or at position 9 were tested for their ability to inactivate the human DNA repair protein, O6-alkylguanine-DNA alkyltransferase. Substitution on the benzene ring was well tolerated although activity varied considerably with structural changes in groups attached to position 9. For this site, activity was preserved with large or small lipophilic groups while introduction of non-carbohydrate polar groups generally reduced activity regardless of their size.