Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6- benzylguanine

Gary T. Pauly, Natalia A. Loktionova, Qingming Fang, Sai Lakshmana Vankayala, Wayne C. Guida, Anthony E. Pegg

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19 Scopus citations


O6-Benzylguanine is an irreversible inactivator of O 6-alkylguanine-DNA alkyltransferase currently in clinical trials to overcome alkyltransferase-mediated resistance to certain cancer chemotherapeutic alkylating agents. In order to produce more soluble alkyltransferase inhibitors, we have synthesized three aminomethyl-substituted O 6-benzylguanines and the three methyl analogs and found that the substitution of aminomethyl at the meta-position greatly enhances inactivation of alkyltransferase, whereas para-substitution has little effect and ortho-substitution virtually eliminates activity. Molecular modeling of their interactions with alkyltransferase provided a molecular explanation for these results. The square of the correlation coefficient (R2) obtained between E-model scores (obtained from GLIDE XP/QPLD docking calculations) vs log(ED50) values via a linear regression analysis was 0.96. The models indicate that the ortho-substitution causes a steric clash interfering with binding, whereas the meta-aminomethyl substitution allows an interaction of the amino group to generate an additional hydrogen bond with the protein.

Original languageEnglish (US)
Pages (from-to)7144-7153
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number22
StatePublished - Nov 27 2008

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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