2-Amino-O4-benzylpteridine derivatives: Potent inactivators of O6-alkylguanine-DNA alkyltransferase

Michael E. Nelson, Natalia A. Loktionova, Anthony E. Pegg, Robert C. Moschel

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

2-Amino-O4-benzylpteridine (1), 2-amino-O4-benzyl-6, 7-dimethylpteridine (2), 2-amino-O4-benzyl-6-hydroxymethylpteridine (4), 2-amino-O4-benzylpteridine-6-carboxylic acid (5), 2-amino-O 4-benzyl-6-formylpteridine (6), and O4-benzylfolic acid (7) are shown to be as potent or more potent inactivators of the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) in vitro than O6-benzylguanine, the prototype alkyltransferase inactivator currently in clinical trials. Additionally, the negatively charged (at physiological pH) inactivators 2-amino-O 4-benzylpteridine-6-carboxylic acid (5) and O4- benzylfolate (7) are far more water soluble than O6-benzylguanine. The activity of O4-benzylfolic acid (7) is particularly noteworthy because it is roughly 30 times more active than O6-benzylguanine against the wild-type alkyltransferase and is even capable of inactivating the P140K mutant alkyltransferase that is resistant to inactivation by O 6-benzylguanine. All the pteridine derivatives except 2-amino-O 4-benzylpteridine-6-carboxylic acid are effective in enhancing cell killing by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the effectiveness of O4-benzylfolate as an adjuvant for cell killing by BCNU appears to be a function of a cell's α-folate receptor expression. Thus, O4-benzylfolate is least effective as an adjuvant in A549 cells (which express little if any receptor), is moderately effective in HT29 cells (which express low levels of the receptor), but is very effective in KB cells (which are known to express high levels of the α-folate receptor). Therefore, O4-benzylfolic acid shows promise as an agent for possible tumor-selective alkyltransferase inactivation, which suggests it may prove to be superior to O6-benzylguanine as a chemotherapy adjuvant.

Original languageEnglish (US)
Pages (from-to)3887-3891
Number of pages5
JournalJournal of Medicinal Chemistry
Volume47
Issue number15
DOIs
StatePublished - Jul 1 2004

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of '2-Amino-O<sup>4</sup>-benzylpteridine derivatives: Potent inactivators of O<sup>6</sup>-alkylguanine-DNA alkyltransferase'. Together they form a unique fingerprint.

  • Cite this