Mechanism of action of the nitrosoureas-V. Formation of O6-(2-fluoroethyl) guanine and its probable role in the crosslinking of deoxyribonucleic acid

William P. Tong; Marion C. Kirk; David B. Ludlum

doi:10.1016/0006-2952(83)90420-3

Mechanism of action of the nitrosoureas-V. Formation of O⁶-(2-fluoroethyl) guanine and its probable role in the crosslinking of deoxyribonucleic acid

William P. Tong, Marion C. Kirk, David B. Ludlum

Cancer Systems Imaging

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

Abstract

DNA which has been exposed to 2-haloethylnitrosoureas has been shown to contain the chemical crosslink 1-(N³-deoxycytidyl), 2-(N¹-deoxyguanosinyl)-ethane [W.P. Tong, M.C. Kirk and D.B. Ludlum, Cancer Res. 43, 3102 (1982)]. We have hypothesized that this structure is formed by an initial attack of a 2-haloethyl group on the 6 position of guanine followed by an intramolecular rearrangement and secondary crosslinking reaction with cytosine. We have now shown that DNA which had been reacted with N-(2-fluoroethyl)-N′-cyclohexyl-N-nitrosourea contained O⁶-(2-fluoroethyl) guanine and have thus demonstrated that the first step in the proposed mechanism occurs. Furthermore, O⁶-(2-fluoroethyl)guanosine hydrolyzed to N¹-(2-hydroxyethyl)guanosine, showing that the necessary intramolar rearrangement occurs. These two observations greatly strengthen the proposed route to DNA crosslinking by the 2-haloethylnitrosoureas.

Original language	English (US)
Pages (from-to)	2011-2015
Number of pages	5
Journal	Biochemical Pharmacology
Volume	32
Issue number	13
DOIs	https://doi.org/10.1016/0006-2952(83)90420-3
State	Published - Jul 1 1983

ASJC Scopus subject areas

Biochemistry
Pharmacology

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@article{8371ee20ce9b48efa1510c856c9e63b3,

title = "Mechanism of action of the nitrosoureas-V. Formation of O6-(2-fluoroethyl) guanine and its probable role in the crosslinking of deoxyribonucleic acid",

abstract = "DNA which has been exposed to 2-haloethylnitrosoureas has been shown to contain the chemical crosslink 1-(N3-deoxycytidyl), 2-(N1-deoxyguanosinyl)-ethane [W.P. Tong, M.C. Kirk and D.B. Ludlum, Cancer Res. 43, 3102 (1982)]. We have hypothesized that this structure is formed by an initial attack of a 2-haloethyl group on the 6 position of guanine followed by an intramolecular rearrangement and secondary crosslinking reaction with cytosine. We have now shown that DNA which had been reacted with N-(2-fluoroethyl)-N′-cyclohexyl-N-nitrosourea contained O6-(2-fluoroethyl) guanine and have thus demonstrated that the first step in the proposed mechanism occurs. Furthermore, O6-(2-fluoroethyl)guanosine hydrolyzed to N1-(2-hydroxyethyl)guanosine, showing that the necessary intramolar rearrangement occurs. These two observations greatly strengthen the proposed route to DNA crosslinking by the 2-haloethylnitrosoureas.",

author = "Tong, {William P.} and Kirk, {Marion C.} and Ludlum, {David B.}",

note = "Funding Information: Acknowledgements-Thisw ork was supportedb y Public Health ServiceG rants CA 20292a nd CA 32171fr om the National Cancer Institute (NCI), National Institutes of Health, Departmento f Health, Education, and Welfare. We thank SuzanneW issel for her editorial assistancea nd SantusS eitz for technicala ssistance.",

year = "1983",

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T1 - Mechanism of action of the nitrosoureas-V. Formation of O6-(2-fluoroethyl) guanine and its probable role in the crosslinking of deoxyribonucleic acid

AU - Tong, William P.

AU - Kirk, Marion C.

AU - Ludlum, David B.

N1 - Funding Information: Acknowledgements-Thisw ork was supportedb y Public Health ServiceG rants CA 20292a nd CA 32171fr om the National Cancer Institute (NCI), National Institutes of Health, Departmento f Health, Education, and Welfare. We thank SuzanneW issel for her editorial assistancea nd SantusS eitz for technicala ssistance.

PY - 1983/7/1

Y1 - 1983/7/1

N2 - DNA which has been exposed to 2-haloethylnitrosoureas has been shown to contain the chemical crosslink 1-(N3-deoxycytidyl), 2-(N1-deoxyguanosinyl)-ethane [W.P. Tong, M.C. Kirk and D.B. Ludlum, Cancer Res. 43, 3102 (1982)]. We have hypothesized that this structure is formed by an initial attack of a 2-haloethyl group on the 6 position of guanine followed by an intramolecular rearrangement and secondary crosslinking reaction with cytosine. We have now shown that DNA which had been reacted with N-(2-fluoroethyl)-N′-cyclohexyl-N-nitrosourea contained O6-(2-fluoroethyl) guanine and have thus demonstrated that the first step in the proposed mechanism occurs. Furthermore, O6-(2-fluoroethyl)guanosine hydrolyzed to N1-(2-hydroxyethyl)guanosine, showing that the necessary intramolar rearrangement occurs. These two observations greatly strengthen the proposed route to DNA crosslinking by the 2-haloethylnitrosoureas.

AB - DNA which has been exposed to 2-haloethylnitrosoureas has been shown to contain the chemical crosslink 1-(N3-deoxycytidyl), 2-(N1-deoxyguanosinyl)-ethane [W.P. Tong, M.C. Kirk and D.B. Ludlum, Cancer Res. 43, 3102 (1982)]. We have hypothesized that this structure is formed by an initial attack of a 2-haloethyl group on the 6 position of guanine followed by an intramolecular rearrangement and secondary crosslinking reaction with cytosine. We have now shown that DNA which had been reacted with N-(2-fluoroethyl)-N′-cyclohexyl-N-nitrosourea contained O6-(2-fluoroethyl) guanine and have thus demonstrated that the first step in the proposed mechanism occurs. Furthermore, O6-(2-fluoroethyl)guanosine hydrolyzed to N1-(2-hydroxyethyl)guanosine, showing that the necessary intramolar rearrangement occurs. These two observations greatly strengthen the proposed route to DNA crosslinking by the 2-haloethylnitrosoureas.

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Mechanism of action of the nitrosoureas-V. Formation of O⁶-(2-fluoroethyl) guanine and its probable role in the crosslinking of deoxyribonucleic acid

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