Synthetic Strategies Towards O6-Substituted Guanine Derivatives and their Application in Medicine

Schirrmacher, Ralf; Schirrmacher, Esther; Mühlhausen, Ute; Kaina, Bernd; Wängler, Björn

doi:10.2174/1570179053545369

Cited by 4 publications

(3 citation statements)

References 63 publications

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“…These oxidizing agents form electrophilic iodine species for subsequent reaction with the aromatic or heteroaromatic system. A first attempt to label SnTGG (8) with CAT under acidic conditions (2 N HCl) resulted in an almost quantitative cleavage of the 131 I-iodinated iodothenyl alcohol at the O 6 -position of guanine. Interestingly, contrasting reports about the acid sensitivity of O 6 -substituted guanines were found in the literature.…”

Section: Resultsmentioning

confidence: 99%

“…[4][5][6][7] The chemistry of these MGMT inhibitors has been reviewed recently. 8 The structural requirements of O 6 -substituted guanines for efficient depletion of human MGMT were demonstrated by Moschel et al 9 They showed that O 6 -benzylguanine (O 6 -BG) and O 6 -(p-chlorobenzyl)guanine are alternative substrates for the enzyme, causing rapid depletion of MGMT in human tumor cell extracts and intact cells. 10 They synthesized and tested a series of O 6 -and S 6 -substituted guanine derivatives for their ability to deplete the human MGMT in cell-free extracts of tumor cells as well as in intact cells.…”

Section: Introductionmentioning

confidence: 99%

“…Since MGMT is one of the most important factors determining resistance to methylating and chloroethylating agents, also causing acquired resistance of tumor cells against these chemotherapeutics, strategies have been developed to suppress MGMT activity in tumors by means of MGMT pseudosubstrates. A great variety of different MGMT inhibitors have been synthesized and evaluated as to their MGMT inhibitory potency. − The chemistry of these MGMT inhibitors has been reviewed recently …”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2005

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2005

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