Kinetics and mechanism of the acid-catalyzed hydrolysis of O6-benzylguanine

Safadi, Muhammad; Bindra, Dilbir S.; Williams, Todd D.; Moschel, Robert C.; Stella, Valentino J.

doi:10.1016/0378-5173(93)90196-m

Cited by 8 publications

(5 citation statements)

References 5 publications

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“…Interestingly, contrasting reports about the acid sensitivity of O 6 -substituted guanines were found in the literature. Safadi et al reported on the instability of O 6 -benzylguanine to acidic conditions, whereas Vaidyanathan et al did not detect any cleavage of the 3-iodobenzyl group from the O 6 -position of guanine using TFA for the deprotection of the N 9 -position, which is explained to be due to a lack of water. Furthermore, they did not detect any decomposition of [ 131 I]IBG ( [ 131 I]11 ) during HPLC purification using 0.1% TFA in water as a cosolvent in contrast to our results.…”

Section: Resultsmentioning

confidence: 98%

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: 98%

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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“…In no case was the formation of 14E or 14Z observed, and no peaks produced from the hydrolysis of 20 were coincident with peak 2. Moschel has reported on the facile solvolytic removal of benzyl groups from the O 6 position of guanine . We believe that the nitrosamine function is being removed from the O 6 position of the guanine derivatives by a pathway involving neighboring group participation as shown in Scheme .…”

Section: Resultsmentioning

confidence: 99%

“…Moschel has reported on the facile solvolytic removal of benzyl groups from the O 6 position of guanine. 39 We believe that the nitrosamine function is being removed from the O 6 position of the guanine derivatives by a pathway involving neighboring group participation as shown in Scheme 7. This process produces the 1,2,3-oxadiazolinium ion, which suffers rapid hydrolysis to 1 under the reaction conditions, and is completely consistent with the experiments of the Michejda group, 22,23 who demonstrated neighboring group participation of the nitroso oxygen in the solvolysis of esters of 1.…”

Section: Resultsmentioning

confidence: 99%

DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

Loeppky

et al. 1996

J. Am. Chem. Soc.

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The reaction of 3-methyl-1,2,3-oxadiazolinium tosylate 10, a close model for a putative reactive intermediate in the carcinogenic activation of ethanol nitrosamines such as (2-hydroxyethyl)methylnitrosamine 1, with various guanine derivatives, including acycloguanosine 12, deoxyguanosine, deoxyguanosine monophosphate, and cyclic guanosine monophosphate, various DNA oligomers, and calf-thymus DNA has been examined to determine whether this compound methylates and hydroxyethylates guanine residues as proposed. In all of the transformations, 7-(2-(methylnitrosamino)ethyl)guanine (14) is the major product, following acidic hydrolysis, and exceeds the formation of 7-methylguanine by ratios ranging from 4:1 to 48:1, depending upon the guanine bearing substrate. O 6-(2-(Methylnitrosamino)ethyl)deoxyguanosine (20) was prepared from the Mitsunobu coupling of 1 and a protected deoxyguanosine derivative. 20 is not produced in the reaction of 10 and deoxyguanosine and decomposes to 1 and guanine upon mild acid treatment, suggesting possible neighboring group participation in its facile hydrolytic cleavage. All of the major products from the reaction of 10 and 12 have been characterized, including the direct alkylation product, 7-(2-(methylnitrosamino)ethyl)acycloguanosine (13), and N 2-(2-(methylnitrosamino)ethyl)guanine, which was independently synthesized. Elucidation of the reactions of DNA with 10 and other electrophiles was facilitated by the development of both partial and total enzymatic hydrolysis assays utilizing 32P-5‘-labeled DNA oligotetramers containing one of each base type and HPLC with radiometric detection. The partial hydrolysis assay gives information as to the type of base being modified, and the total hydrolysis assay permits a determination of the number of adducts produced for a given base. The assays permit a comparison between reactions where the same type of base adduct could be expected. Comparisons of the reactions of ethylene oxide and 10 using this methodology showed that 10 does not hydroxyethylate guanine in DNA.

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“…Loeppky et al [82] investigated the formation of DNA guanine adducts from 3-methyl-1,2,3-oxadiazolium ions and reported the synthesis of an O 6 -deoxyguanosine-nitrosamine adduct (28) as an intermediate in the preparation of O 6 -(2-(methylnitrosoamino) ethyl)deoxyguanosine (29). Standard Mitsunobu-conditions were applied and the O 6 -coupled nitrosamine group was shown to be very unstable under acidic conditions which is in accordance with the facile solvolytic removal of benzyl groups from the O 6 -position of guanines [83]. Some additional applications of the Mitsunobu alkylation have been reported in literature which do not differ significantly from the ones described above.…”

Section: Miscellaneous Precursors and Methodsmentioning

confidence: 84%

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

Schirrmacher

Mühlhausen³

et al. 2005

COS

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Kinetics and mechanism of the acid-catalyzed hydrolysis of O6-benzylguanine

Cited by 8 publications

References 5 publications

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

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

DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

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

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Kinetics and mechanism of the acid-catalyzed hydrolysis of O6-benzylguanine

Cited by 8 publications

References 5 publications

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

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

DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

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

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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

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