β-Glucuronidase-cleavable prodrugs of O6-benzylguanine and O6-benzyl-2′-deoxyguanosine

Guangping Wei, Natalia A. Loktionova, Anthony Pegg, Robert C. Moschel

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Glucuronic acid linked prodrugs of O6-benzylguanine and O 6-benzyl-2′-deoxyguanosine were synthesized. The prodrugs were found to be quite stable at physiological pH and were more than 200-fold less active as inactivators of O6-alkylguanine-DNA alkyltransferase (alkyltransferase) than either O6-benzylguanine or O 6-benzyl-2′-deoxyguanosine. β-Glucuronidase from both Escherichia coli and bovine liver cleaved the prodrugs efficiently to release O6-benzylguanine and O6-benzyl-2′-deoxyguanosine, respectively. In combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), the prodrugs were not effective adjuvants for HT29 cell killing. However, as expected, incubation of these prodrugs with β-glucuronidase in the culture medium led to much more efficient cell killing by BCNU as a result of the liberation of the more potent inactivators, O6-benzylguanine and O6-benzyl-2′-deoxyguanosine. These prodrugs may be useful for prodrug monotherapy of necrotic tumors that liberate β-glucuronidase or for antibody-directed enzyme prodrug therapy with antibodies that can deliver β-glucuronidase to target tumor cells.

Original languageEnglish (US)
Pages (from-to)256-261
Number of pages6
JournalJournal of Medicinal Chemistry
Volume48
Issue number1
DOIs
Publication statusPublished - Jan 13 2005

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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