Potentiation of the Cytotoxicity of Chloroethylnitrosourea by O^6-Arylmethylguanines

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It was reported recently that monomeric O^6-benzylguanine (1) acts as an alternative substrate for a DNA repair enzyme, O^6-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 O^6-benzylguanine derivatives with AGT and to obtain greater AGT depletion, we synthesized the following O^6-arylmethylguanine derivatives and related compounds : O^6-(4-, 3- and 2-fluorobenzyl) guanines (2,3,4), O^6-(4-, 3- and 2-trifluoromethylbenzyl) guanines (5,6,7), O^6-(4-, 3- and 2-pyridylmethyl) guanines (8,9,10), O^6-(2- and 1-naphthylmethyl) guanines (11,12), O^6-biphenylmethylguanine (13), S and Se analogues of O^6-benzylguanine (14,15) and O^6-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 O^6-benzyl group plays an important role in the interaction of O^6-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 O^6-benzylguanine derivatives and the chemical characteristics of their substituents.
社団法人日本薬学会の論文
1995-03-15

Potentiation of the Cytotoxicity of Chloroethylnitrosourea by O^6-Arylmethylguanines

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