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-nitrosourea (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 α position of the benzyl group, and compound 10, the α-nitrogen analogue of 1, were almost completely devoid of potentiating activity. These results suggest that the α-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. © 1995, The Pharmaceutical Society of Japan. All rights reserved.