title: Potentiation of the cytotoxicity of chloroethylnitrosourea by O6-arylmethylguanines.
abstract: It was reported recently that monomeric O6-benzylguanine (1) acts as an alternative substrate for a DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (AGT), and that therefore pretreatment of cells with 1 induces depletion of AGT resulting in an enhanced cytotoxic response to alkylating antitumor agents. In order to study the interaction of O6-benzylguanine derivatives with AGT and to obtain greater AGT depletion, we synthesized the following O6-arylmethylguanine derivatives and related compounds: O6-(4-, 3- and 2-fluorobenzyl)guanines (2, 3, 4), O6-(4-, 3- and 2-trifluoromethylbenzyl)guanines (5, 6, 7), O6-(4-, 3- and 2-pyridylmethyl)guanines (8, 9, 10), O6-(2- and 1-naphthylmethyl)guanines (11, 12), O6-biphenylmethylguanine (13), S and Se analogues of O6-benzylguanine (14, 15) and O6-phenylguanine (16). Ten of these are new compounds. All these compounds were tested for their potentiation of N'-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(2-chloroethyl)-N-nitrosou rea (ACNU) cytotoxicity using HeLa S3 and C6-1 cells. Compounds 2, 3, 5, 8, 9, 11 and 13 were active, as was 1. Compounds 7 and 12, with a substituent at the alpha position of the benzyl group, and compound 10, the alpha-nitrogen analogue of 1, were almost completely devoid of potentiating activity. These results suggest that the alpha-position of the O6-benzyl group plays an important role in the interaction of O6-benzylguanines with AGT. Of the other compounds, 4 and 6 exhibited very weak activity and 14, 15 and 16 were inactive. Possible reasons for these differences in activity are discussed in relation to the biomimetic dealkylation rates of O6-benzylguanine derivatives and the chemical characteristics of their substituents.
authors.affiliation: Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kohda
authors.forename: I
authors.initials: I
authors.lastname: Terashima
authors.forename: K
authors.initials: K
authors.lastname: Koyama
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.forename: K
authors.initials: K
authors.lastname: Mineura
mesh_terms: D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism; D015376:Nimustine / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010636:Phenols / Q000378:metabolism; D000091402:Prohibitins; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C000717331:PHB2 protein, human; D010636:Phenols; D000091402:Prohibitins; D015376:Nimustine; D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase