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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

Lookup NU author(s): Professor Roger Griffin, Dr Christine Arris, Dr Christine Bleasdale, Professor Alan Calvert, Professor Nicola Curtin, Professor Herbie Newell, Professor Bernard Golding

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Abstract

A series of O6-allyl- and O6-(2-oxoalkyl)guanines were synthesized and evaluated, in comparison with the corresponding O6-alkylguanines; as potential inhibitors of the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Simple O6-alkyl- and O6-cycloalkylguanines were weak AGT inactivators compared with O6-allylguanine (IC50 = 8.5 ± 0.6 μM)with IC50 values ranging from 100 to 1000 μM. The introduction of substituents at C-2 of the allyl group of O6-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O6-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 μM). O6-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC50 = 0.55 ± 0.02 μM) and 1-cyclopentenylmethylguanine(IC50 = 0.39 ± 0.04 μM) exhibiting potency approaching that of the benchmark AGT inhibitor O6-benzylguanine (IC50 = 0.18 ± 0.02 μM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC50 = 0.20 ± 0.07 μM) 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 O6-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O6-substituent of each compound makes similar binding interactions within the active site of AGT.


Publication metadata

Author(s): Griffin, R. J., Arris, C. E., Bleasdale, C. , Boyle, F., Calvert, A. H., Curtin, N. J., Dalby, C., Kanugula, S., Lembicz, N., Newell, D. R., Pegg, A., Golding, B. T.

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2000

Volume: 43

Issue: 22

Pages: 4071-4083

Print publication date: 02/11/2000

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm000961o

DOI: 10.1021/jm000961o

PubMed id: 11063604


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