Inactivation of O6-alkylguanine-DNA alkyltransferase by folate esters of O6-benzyl-2′-deoxyguanosine and of O 6-[4-(hydroxymethyl)benzyl]guanine

Sahar Javanmard, Natalia A. Loktionova, Qingming Fang, Gary T. Pauly, Anthony E. Pegg, Robert C. Moschel

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13 Scopus citations

Abstract

O6-Alkylguanine-DNA alkyltransferase (alkyltransferase) provides an important source of resistance to some cancer chemotherapeutic alkylating agents. Folate ester derivatives of O6-benzyl-2′-deoxyguanosine and of O6-[4-(hydroxymethyl)benzyl]guanine were synthesized and tested for their ability to inactivate human alkyltransferase. Inactivation of alkyltransferase by the γ-folate ester of O6- [4-(hydroxymethyl)benzyl] guanine was similar to that of the parent base. The γ-folate esters of O6-benzyl-2′-deoxyguanosine were more potent alkyltransferase inactivators than the parent nucleoside. The 3′-ester was considerably more potent than the 5′-ester and was more than an order of magnitude more active than O6-benzylguanine, which is currently in clinical trials to enhance therapy with alkylating agents. They were also able to sensitize human tumor cells to killing by 1,3-bis(2- chloroethyl)-1-nitrosourea, with O6-benzyl-3′-O-(γ-folyl) -2′-deoxyguanosine being most active. These compounds provide a new class of highly water-soluble alkyltransferase inactivators and form the basis to construct more tumor-specific and potent compounds targeting this DNA repair protein.

Original languageEnglish (US)
Pages (from-to)5193-5201
Number of pages9
JournalJournal of Medicinal Chemistry
Volume50
Issue number21
DOIs
StatePublished - Oct 18 2007

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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