Synthesis of 131I-Labeled Glucose-Conjugated Inhibitors of O 6-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging

Autoren

Ute Mühlhausen
Ralf Schirrmacher
Markus Piel
Bernd Lecher
Manuela Briegert
Andrea Piee-Staffa
Bernd Kaina
Frank Rösch

DOI

10.1021/jm050588q

eISSN

1520-4804

ISSN

0022-2623

Ausgabe der Veröffentlichung

1

Zeitschrift

Journal of Medicinal Chemistry

Sprache

en

Online publication date

2005

Paginierung

263 - 272

Datum der Veröffentlichung

2006

Status

Published

Herausgeber

American Chemical Society (ACS)

Herausgeber URL

http://dx.doi.org/10.1021/jm050588q

Datum der Datenerfassung

2023

Titel

Synthesis of 131I-Labeled Glucose-Conjugated Inhibitors of O6-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging

Ausgabe der Zeitschrift

49

Data source: Crossref

Abstract

O(6)-Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C(8)-alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O(6)-(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O(6)-(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC(50) values) of 0.8 and 0.45 microM for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the (131)I-(hetero)arylmethylene group at the O(6)-position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [(131)I]I(-) were performed with radiochemical yields of >70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [(131)I]ITGG, [(131)]IBGG, [(131)I]ITG, and [(131)I]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [(131)I]IBG and [(131)I]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.

Addresses

Institute of Nuclear Chemistry, University of Mainz, Germany.

Autoren

Ute Mühlhausen
Ralf Schirrmacher
Markus Piel
Bernd Lecher
Manuela Briegert
Andrea Piee-Staffa
Bernd Kaina
Frank Rösch

DOI

10.1021/jm050588q

eISSN

1520-4804

Externe Identifier

PubMed Identifier: 16392811

Open access

false

ISSN

0022-2623

Ausgabe der Veröffentlichung

1

Zeitschrift

Journal of medicinal chemistry

Schlüsselwörter

Hela Cells
Animals
Humans
Mice
Mice, Nude
Iodine Isotopes
Guanine
O(6)-Methylguanine-DNA Methyltransferase
Glucose
Antineoplastic Agents
Enzyme Inhibitors
Transplantation, Heterologous
Xenograft Model Antitumor Assays
Molecular Structure
Structure-Activity Relationship
Time Factors
In Vitro Techniques

Sprache

eng

Medium

Print

Paginierung

263 - 272

Datum der Veröffentlichung

2006

Status

Published

Datum der Datenerfassung

2006

Titel

Synthesis of 131I-labeled glucose-conjugated inhibitors of O6-methylguanine-DNA methyltransferase (MGMT) and comparison with nonconjugated inhibitors as potential tools for in vivo MGMT imaging.

Sub types

Comparative Study
Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

49

Data source: Europe PubMed Central

Abstract

O(6)-Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C(8)-alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O(6)-(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O(6)-(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC(50) values) of 0.8 and 0.45 microM for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the (131)I-(hetero)arylmethylene group at the O(6)-position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [(131)I]I(-) were performed with radiochemical yields of >70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [(131)I]ITGG, [(131)]IBGG, [(131)I]ITG, and [(131)I]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [(131)I]IBG and [(131)I]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.

Autoren

Ute Mühlhausen
Ralf Schirrmacher
Markus Piel
Bernd Lecher
Manuela Briegert
Andrea Piee-Staffa
Bernd Kaina
Frank Rösch

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/16392811

DOI

10.1021/jm050588q

ISSN

0022-2623

Ausgabe der Veröffentlichung

1

Zeitschrift

J Med Chem

Schlüsselwörter

Animals
Antineoplastic Agents
Enzyme Inhibitors
Glucose
Guanine
HeLa Cells
Humans
In Vitro Techniques
Iodine Isotopes
Mice
Mice, Nude
Molecular Structure
O(6)-Methylguanine-DNA Methyltransferase
Structure-Activity Relationship
Time Factors
Transplantation, Heterologous
Xenograft Model Antitumor Assays

Sprache

eng

Country

United States

Paginierung

263 - 272

Datum der Veröffentlichung

2006

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2006

Titel

Synthesis of 131I-labeled glucose-conjugated inhibitors of O6-methylguanine-DNA methyltransferase (MGMT) and comparison with nonconjugated inhibitors as potential tools for in vivo MGMT imaging.

Sub types

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

49

Data source: PubMed

Autoren

Ute Mühlhausen
Ralf Schirrmacher
Markus Piel
Bernd Lecher
Manuela Briegert
Andrea Piee-Staffa
Bernd Kaina
Frank Rösch

Zeitschrift

Journal of medicinal chemistry

Artikelnummer

1

Paginierung

263 - 272

Datum der Veröffentlichung

2006

Herausgeber

ACS Publications

Datum der Datenerfassung

2021

Titel

Synthesis of 131I-Labeled Glucose-Conjugated Inhibitors of O 6-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging

Sub types

article

Ausgabe der Zeitschrift

49

Data source: Manual