A strategy for selective O(6)-alkylguanine-DNA alkyltransferase depletion under hypoxic conditions.

Chemical Biology & Drug Design
P G PenkethA C Sartorelli

Abstract

Cellular resistance to chemotherapeutics that alkylate the O-6 position of guanine residues in DNA correlates with their O(6)-alkylguanine-DNA alkyltransferase activity. In normal cells high [O(6)-alkylguanine-DNA alkyltransferase] is beneficial, sparing the host from toxicity, whereas in tumor cells high [O(6)-alkylguanine-DNA alkyltransferase] prevents chemotherapeutic response. Therefore, it is necessary to selectively inactivate O(6)-alkylguanine-DNA alkyltransferase in tumors. The oxygen-deficient compartment unique to solid tumors is conducive to reduction, and could be utilized to provide this selectivity. Therefore, we synthesized 2-nitro-6-benzyloxypurine, an analog of O(6)-benzylguanine in which the essential 2-amino group is replaced by a nitro moiety, and 2-nitro-6-benzyloxypurine is >2000-fold weaker than O(6)-benzylguanine as an O(6)-alkylguanine-DNA alkyltransferase inhibitor. We demonstrate oxygen concentration sensitive net reduction of 2-nitro-6-benzyloxypurine by cytochrome P450 reductase, xanthine oxidase, and EMT6, DU145, and HL-60 cells to yield O(6)-benzylguanine. We show that 2-nitro-6-benzyloxypurine treatment depletes O(6)-alkylguanine-DNA alkyltransferase in intact cells under oxygen-deficient conditi...Continue Reading

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Citations

Sep 18, 2015·Molecular Pharmaceutics·Karl-Heinz TomaszowskiBernd Kaina
Jul 14, 2018·Future Medicinal Chemistry·Guohui SunYongzhen Peng
Mar 14, 2013·The Biochemical Journal·Jiechuang SuWilliam R Wilson
Dec 19, 2019·International Journal of Molecular Sciences·Weinan XiaoRugang Zhong
Jul 31, 2021·Nature Reviews. Clinical Oncology·Dean C SingletonWilliam R Wilson

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