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

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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.

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