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Substitution of Aminomethyl at the Meta-Position Enhances the Inactivation of O-6-Alkylguanine-DNA Alkyltransferase by O-6-Benzylguanine

  1. Author:
    Pauly, G. T.
    Loktionova, N. A.
    Fang, Q. M.
    Vankayala, S. L.
    Guida, W. C.
    Pegg, A. E.

  2. Author Address

    Loktionova, Natalia A.; Fang, Qingming, Pegg, Anthony E.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Pauly, Gary T.] NCI, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. [Loktionova, Natalia A.; Fang, Qingming, Pegg, Anthony E.] Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA. [Vankayala, Sai Lakshmana, Guida, Wayne C.] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Vankayala, Sai Lakshmana, Guida, Wayne C.] Univ S Florida, Ctr Mol Divers Drug Design Discovery & Delivery, Tampa, FL 33620 USA. [Guida, Wayne C.] H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, Tampa, FL 33612 USA.
    1. Year: 2008
  2. Journal: Journal of Medicinal Chemistry
    1. 51
    2. 22
    3. Pages: 7144-7153
  4. Type of Article: Article
  1. Abstract:

    O-6-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 (R-2) 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.

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External Sources

  1. PMID: 18973327

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