Potentiation of the cytotoxicity of chloroethylnitrosourea by O6-arylmethylguanines

Article abstract of DOI:10.1248/bpb.18.424

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, me 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] (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 a position of the benzyl group, and compound 10, the a-nitrogen analogue of 1, were almost completely devoid of potentiating activity. These results suggest that the a-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.

Full text of DOI:10.1248/bpb.18.424

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