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 Pegg

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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
Volume51
Issue number22
DOIs
StatePublished - Nov 27 2008

Fingerprint

Alkyl and Aryl Transferases
O(6)-Methylguanine-DNA Methyltransferase
Alkylating Agents
Hydrogen
Linear Models
Regression Analysis
Clinical Trials
DNA alkyltransferase
O(6)-benzylguanine
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Pauly, Gary T. ; Loktionova, Natalia A. ; Fang, Qingming ; Vankayala, Sai Lakshmana ; Guida, Wayne C. ; Pegg, Anthony. / Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6- benzylguanine. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 22. pp. 7144-7153.
@article{fbc2d6373f5d4910aa6f7e50f33f9d49,
title = "Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6- benzylguanine",
abstract = "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.",
author = "Pauly, {Gary T.} and Loktionova, {Natalia A.} and Qingming Fang and Vankayala, {Sai Lakshmana} and Guida, {Wayne C.} and Anthony Pegg",
year = "2008",
month = "11",
day = "27",
doi = "10.1021/jm800675p",
language = "English (US)",
volume = "51",
pages = "7144--7153",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6- benzylguanine. / Pauly, Gary T.; Loktionova, Natalia A.; Fang, Qingming; Vankayala, Sai Lakshmana; Guida, Wayne C.; Pegg, Anthony.

In: Journal of Medicinal Chemistry, Vol. 51, No. 22, 27.11.2008, p. 7144-7153.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6- benzylguanine

AU - Pauly, Gary T.

AU - Loktionova, Natalia A.

AU - Fang, Qingming

AU - Vankayala, Sai Lakshmana

AU - Guida, Wayne C.

AU - Pegg, Anthony

PY - 2008/11/27

Y1 - 2008/11/27

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=56749105982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=56749105982&partnerID=8YFLogxK

U2 - 10.1021/jm800675p

DO - 10.1021/jm800675p

M3 - Article

VL - 51

SP - 7144

EP - 7153

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -