Resistance-modifying agents.: 8.: Inhibition of O6-alkylguanine-DNA alkyltransferase by O6-alkenyl-, O6-cycloalkenyl-, and O6-(2-oxoalkyl)guanines and potentiation of temozolomide cytotoxicity in vitro by O6-(1-cyclopentenylmethyl)guanine

被引:51
作者
Griffin, RJ
Arris, CE
Bleasdale, C
Boyle, FT
Calvert, AH
Curtin, NJ
Dalby, C
Kanugula, S
Lembicz, NK
Newell, DR
Pegg, AE
Golding, BT
机构
[1] Newcastle Univ, Dept Chem, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[2] Univ Newcastle, Sch Med, Canc Res Unit, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[3] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England
[4] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA
[5] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA
关键词
D O I
10.1021/jm000961o
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of O-6-allyl- and O-6-(2-oxoalkyl)guanines were synthesized and evaluated, in comp ari son with the corresponding O-6-alkylguanines, as potential inhibitors of the DNA-repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). Simple O-6-alkyl- and O-6-cycloalkylguanines were weak AGT inactivators compared with O-6-allylguanine (IC50 = 8.5 +/- 0.6 muM) With IC50 values ranging from 100 to 1000 muM. The introduction of substituents at C-2 of the allyl group of O-6-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O-6-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 muM) O-6-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC50 = 0.55 +/- 0.02 muM) and 1-cyclopentenylmethylguanine (IC50 = 0.39 +/- 0.04 muM) exhibiting potency approaching that of the benchmark AGT inhibitor O-6-benzylguanine (IC50 = 0.18 +/- 0.02 muM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC50 = 0.20 +/- 0.07 muM) and potentiated the cytotoxicity of the monomethylating antitumor agent Temozolomide by approximately 3- and 10-fold, respectively, in the HT29 and Colo205 tumor cell lines. The observation that four mutant AGT enzymes resistant to O-6-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O-6-substituent of each compound makes similar binding interactions within the active site of AGT.
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页码:4071 / 4083
页数:13
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