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• W2139055210 abstract "The DNA repair protein <i>O</i>⁶-methylguanine-DNA methyltransferase (MGMT) is an important suicide enzyme involved in the defense against <i>O</i>⁶-alkylating mutagens. It also plays a role in the resistance of tumors to anticancer drugs targeting the <i>O</i>⁶-position of guanine, such as temozolomide and fotemustine. Several potent MGMT inhibitors have been developed sensitizing cells to <i>O</i>⁶-alkylating agents. Aimed at targeting MGMT inhibitors to tumor cells, we synthesized MGMT inhibitory compounds conjugated with glucose to improve uptake in tumor cells. Here, we compared <i>O</i>⁶-benzylguanine, <i>O</i>⁶-2-fluoropyridinylmethylguanine (O⁶FPG), <i>O</i>⁶-3-iodobenzylguanine, <i>O</i>⁶-4-bromothenylguanine, and <i>O</i>⁶-5-iodothenylguanine with the corresponding C8-linker β-d-glucose derivatives. All glucose conjugated inhibitors were 3- to 5-fold less effective than the corresponding nonconjugated drugs as to MGMT inhibition that was measured in cell extracts (in vitro) and cultivated HeLaS3 cells (in vivo). Except for O⁶FPG, IC₅₀ values of the guanine derivatives applied in vitro and in vivo were correlated. A similar correlation was not obvious for the corresponding glucosides, indicating differences in cellular uptake. C8-α-d-glucosides were less effective than β-glucosides. From the newly developed glucose-conjugated inhibitors tested, <i>O</i>⁶-4-bromothenylguanine-C8-β-d-glucoside (O⁶BTG-C8-βGlu) was most potent in inhibiting MGMT both in vitro and in vivo. At a concentration of 0.1 μM, it inhibited cellular MGMT to completion. It was not toxic, even when applied chronically to cells at high dose (up to 20 μM). O⁶BTG-C8-βGlu strongly potentiated the killing effect of fotemustine and temozolomide, causing reversal from MGMT+ to MGMT– phenotype. Therefore, O⁶BTG-C8-βGlu seems to be especially suitable for approaching MGMT inhibitor targeting in tumor therapy." @default.
• W2139055210 created "2016-06-24" @default.
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• W2139055210 date "2004-07-13" @default.
• W2139055210 modified "2023-10-16" @default.
• W2139055210 title "Inhibition of <i>O</i>⁶-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death" @default.
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• W2139055210 doi "https://doi.org/10.1124/jpet.104.071316" @default.
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