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A Strategy for Selective O 6 ‐ Alkylguanine‐DNA Alkyltransferase Depletion Under Hypoxic Conditions
Author(s) -
Penketh Philip G.,
Shyam Krishnamurthy,
Baumann Raymond P.,
Ishiguro Kimiko,
Patridge Eric V.,
Zhu Rui,
Sartorelli Alan C.
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2012.01401.x
Subject(s) - o 6 methylguanine dna methyltransferase , guanine , dna , biochemistry , chemistry , biology , microbiology and biotechnology , methyltransferase , nucleotide , methylation , gene
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 conditions and selectively sensitizes cells to laromustine (an agent that chloroethylates the O ‐6 position of guanine) under oxygen‐deficient but not normoxic conditions. 2‐Nitro‐6‐benzyloxypurine represents a proof of concept lead compound; however, its facile reduction (E 1/2 – 177 mV versus Ag/AgCl) may result in excessive oxidative stress and/or the generation of O 6 ‐alkylguanine‐DNA alkyltransferase inhibitors in normoxic regions in vivo .