Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine |
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Authors: | Pauly Gary T Loktionova Natalia A Fang Qingming Vankayala Sai Lakshmana Guida Wayne C Pegg Anthony E |
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Institution: | Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, P.O. Box B, Building 538, Frederick, Maryland 21702, USA. |
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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(ED(50)) 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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