Differential inactivation of O6-methylguanine-DNA methyltransferase activity by O6-arylmethylguanines.
Activity of O6-methylguanine-DNA methyltransferase (MGMT) is well related with drug resistance of tumor cells to chloroethylnitrosoureas (CENUs), because MGMT removes CENU-induced O6-alkylguanines in DNA by accepting the alkyl group at a cysteine moiety. Inactivation of MGMT is a feasible way to overcome MGMT-related resistance of tumor cells to CENUs. O6-Benzylguanine is known to be a strong depleter of MGMT. We previously reported the potentiation effect of O6-arylmethylguanine derivatives on cytotoxicity of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), a CENU, for HeLa S3 cells. In this study, we tested the activity of these O6-arylmethylguanine derivatives as depleters of MGMT using HeLa S3 cell-free extract. The O6-arylmethylguanine derivatives tested were O6-benzylguanine (1), O6-(4-, 3-, and 2-fluorobenzyl)guanines (2-4), O6-(4, 3-, and 2-trifluoromethylbenzyl)guanines (5-7), O6-(4-, 3-, and 2-pyridylmethyl)guanines (8-10), and O6-(2- and 1-naphtylmethyl)guanines (11,12). Among these, compounds 1-3, 5, 8, 9 and 11 showed a strong MGMT depletion activity, whereas compounds 4, 6, 7, 10 and 12 were inactive. These inactive compounds, except for 6, have a substituent at the alpha position of the benzyl group (4, 7, 12) or are an alpha nitrogen analogue of 1 (10). There was a good relation (r = -0.856, p < 0.001) between the MGMT depletion activity of O6-arylmethylguanine derivatives and their potentiation activity of ACNU cytotoxicity. These results suggest that the alpha position of the benzyl group plays an important role in the interaction of O6-arylmethylguanine derivatives with MGMT to result in the inactivation of MGMT. Potent MGMT inactivators (1-3, 5, 8, 9, 11) sensitize tumor cells to CENU chemotherapy.
Mineura
K
K
Neurosurgical Service, Akita University Hospital, Japan.
Fukuchi
M
M
Kowada
M
M
Terashima
I
I
Kohda
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D015376:Nimustine / Q000633:toxicity; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015376:Nimustine; D006147:Guanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase