Inter-strand crosslinking of DNA by nitrogen mustard

Kohn, Kurt W.; Spears, Carlos; Doty, Paul

doi:10.1016/s0022-2836(66)80004-9

Cited by 182 publications

(55 citation statements)

References 25 publications

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“…The in vitro DNA interstrand crosslinking gel assay employed in the present investigation is very sensitive, accurate enough for detailed time-course experiments, and particularly useful for agents such as the dimethane sulphonates since previous attempts to identify interstrand crosslinking after busulphan using classical physicochemical techniques such as resistance to thermal denaturation of DNA (Kohn et al, 1966), caesium chloride gradients (Verly & Brakier, 1969), and dispersion of DNA in high salt concentrations (Alexander & Lett, 1960) failed due to both their insensitivity and the low reactivity of busulphan with isolated DNA (Brookes & Lawley, 1961).…”

Section: Discussionmentioning

confidence: 99%

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates

Ponti

Souhami²,

Fox³

et al. 1991

Br J Cancer

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Summary Members of the homologous series of alkanediol dimethanesulphonates of general formula H3C.SO20.(CH2)n.O.SO2.CH3 have been tested for their ability to produce DNA interstrand crosslinking and DNA sequence selectivity of guanine-N7 alkylation. In a sensitive crosslinking gel assay the efficiency of DNA interstrand crosslink formation, dependent on the ability of the alkylating moiety to span critical nucleophilic distances within the DNA, was found at 6 h to be 1,6-hexanediol dimethanesulphonate (Hexa-DMS) (n = 6) > methylene dimethanesulphonate (MDMS) (n = 1) > 1,8-octanediol dimethanesulphonate (Octa-DMS) (n = 8) > Busulphan (n = 4). The DNA interstrand crosslinking produced by MDMS was not due to either of its hydrolysis products, formaldehyde or methanesulphonic acid (MSA). In contrast the extent of monoalkylation at guanine-N7 as determined by a modified DNA sequencing technique was found to be Busulphan>>Hexa-DMS = Octa-DMS, with a sequence selectivity somewhat less than that of other chemotherapeutic alkylating agents such as nitrogen mustards. MDMS at high levels induced a non-specific depurination as a result of the reduction in pH resulting from MSA release. More strikingly MDMS (and MSA) produced a single strong site of guanine reaction (depurination) in a guanine-rich 276 base pair fragment of pBR322 DNA in the sequence of 5'-ATGGTGG-3'. This was observed when non-specific depurination was negligible and was not seen with formic acid. Thus structurally similar alkylating agents can differ in their type and extent of DNA monoalkylation and interstrand crosslinking, and in some cases (e.g. MDMS/MSA) produce reactions with a high degree of selectivity.

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Section: Discussionmentioning

confidence: 99%

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates

Ponti

Souhami²,

Fox³

et al. 1991

Br J Cancer

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“…Exposure of parental A2780 cells, but not of A2780(100) to 100 mM CBL resulted in degradation E ect of CBL treatment on the constitutive and induced levels of DNA repair proteins in A2780 and A2780 (100) The major, primary DNA adduct of CBL is 7-alkylguanine which in a second step reaction generate the cytotoxic crosslinks (Kohn et al, 1966). Repair of 7-alkylguanine by N-methylpurine-DNA glycosylase (MPG) would prevent cytotoxicity.…”

Section: Loss Of Mitochondrial Membrane Integrity Due To Drug Treatmentmentioning

confidence: 99%

Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins

et al. 2000

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“…By using la- (9). in an attempt to determine the in vivo distribution of belled fluorine attached to the ethylene group, we might also BCNU we recently labelled BCNU with 1 1~ in the carbonyl obtain information On the interstrand crosslinking of related group (10) and with I3N in the nitroso group (1 I), and studied nitrosoureas with DNA (14,15). Since these BCNU analogs their metabolic decomposition.…”

Section: Because Of the Longer Half-life Of Fluorine-18 (Trlr = 110mentioning

confidence: 99%

“…(h) Synthesis of CEU (14) (Fig. 3 ) To a stirred solution of 2-chloroethylisocyanate (13) (1.0 g, 10 mmol) in ether (3 mL) was added dropwise a solution of aziridine (473 mg, 11 mmol) in ether (2 mL).…”

Section: (B) Synthesis Of I-(2-flrcoroettzyl)-3-et/zylet~e Urea (Feu)mentioning

confidence: 99%

“…The mixture was kept in a 0°C bath for 30 min. Evaporation of the solvent under reduced pressure gave an 82% yield of CEU (14), which was used without further purification in the subsequent step; 'H nmr (acetone-d6), 6: 3.1 (s, 4H, aziridine group), 3.5 (m, 4H, -CH2-CH2-), 6.1 (bs, IH, -N-H) ppm.…”

Section: (B) Synthesis Of I-(2-flrcoroettzyl)-3-et/zylet~e Urea (Feu)mentioning

confidence: 99%

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Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas

Farrokhzad¹,

Dikšić²,

Yamamoto³

et al. 1984

Can. J. Chem.

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18F-labelled 1,3-bis-(2-fluoroethyl) nitrosourea (18F-BFNU) (9) and 1-(2-chloroethyl)-3-(2-fluoroethyl) nitrosourea (18F-CFNU) (isomeric mixture, 11,12) were synthesized by nucleophilic attack of 18F-labelled tetra-n-butylammonium fluoride on the aziridine ring of 1,3-substituted ureas. Diethyleneurea (DEU) (5), 1-(2-fluoroethyl)-3-ethyleneurea (FEU) (7), and 1-(2-chloroethyl)-3-ethyleneurea (CEU) (14) were used as starting materials in the synthesis. Nitrosation of 18F-labelled 1,3-bis-(2-fluoroethyl) urea (18F-BFU) (6) produced 18F-BFNU with a radiochemical yield of 5–10%. Nitrosation of 18F-labelled 1-(2-chloroethyl)-3-(2-fluoroethyl) urea (18F-CFU) (15) gave 18F-CFNU as a mixture of two isomers. Geometrical isomers of CFNU were separated by hplc, and the radiochemical yield of the two isomers ranged from 8% to 15%, with a radiochemical purity exceeding 96%. Syntheses, which took about 60 min, yielded products with specific activity of 680 mCi/mmol when n-Bu4N+F− was used, or 300 mCi/mmol when HF was used to complete the opening of the aziridine ring.

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Inter-strand crosslinking of DNA by nitrogen mustard

Cited by 182 publications

References 25 publications

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates

Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins

Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas

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Inter-strand crosslinking of DNA by nitrogen mustard

Cited by 182 publications

References 25 publications

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates

Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins

Synthesis of 18F-labelled 2-fluoroethyl-nitrosoureas

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Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas