Reactions of N,N-Bis(2-chloroethyl)-p-aminophenylbutyric Acid (Chlorambucil) with 2‘-Deoxyguanosine

Florea-Wang, Diana; Haapala, Elina; Mattinen, Jorma; Hakala, Kristo; Vilpo, Juhani; Hovinen, Jari

doi:10.1021/tx000249u

Cited by 23 publications

(34 citation statements)

References 23 publications

(30 reference statements)

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“…According to the observed isotopic distribution, the molecule still had one Cl-atom left, in accord with the structure proposed. Substance 8 showed the M þ signal at m/z 578.4, in accord with alkylation at both N(7) and N(9); the proposed structure was further supported by its lability under basic conditions [11].…”

Section: H-nmr Analyses Are Collected Inmentioning

confidence: 76%

Reactions of {4‐[Bis(2‐chloroethyl)amino]phenyl}acetic Acid (Phenylacetic Acid Mustard) with 2′‐Deoxyribonucleosides

Florea-Wang

Ijäs

Hakala

et al. 2007

Chemistry & Biodiversity

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Phenylacetic acid mustard (PAM; 2), a major metabolite of the anticancer agent chlorambucil (CLB; 1), was allowed to react with 2'-deoxyadenosine (dA), 2'-deoxyguanosine (dG), 2'-deoxycytidine (dC), 2'-deoxy-5-methylcytidine (dMeC), and thymidine (T) at physiological pH (cacodylic acid, 50% base). The reactions were followed by HPLC and analyzed by HPLC/MS and/or (1)H-NMR techniques. Although the predominant reaction observed was hydrolysis of PAM, 2 also reacted with various heteroatoms of the nucleosides to give a series of products: compounds 5-31. PAM (2) was found to be hydrolytically slightly more stable than CLB (1). The principal reaction sites of 2 with dA, dG, and with all pyrimidine nucleosides were N(1), N(7), and N(3), resp. Also, several other adducts were detected and characterized. There was no significant difference in the reactivity of 1 and 2 with dG, dA or T, but the N(3) dC-PAM adduct was deaminated easier than the corresponding CLB derivative. The role of PAM-2'-deoxyribonucleoside adducts on the cytotoxic and mutagenic properties of CLB (1) is discussed.

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Section: H-nmr Analyses Are Collected Inmentioning

confidence: 76%

Reactions of {4‐[Bis(2‐chloroethyl)amino]phenyl}acetic Acid (Phenylacetic Acid Mustard) with 2′‐Deoxyribonucleosides

Florea-Wang

Ijäs

Hakala

et al. 2007

Chemistry & Biodiversity

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“…The main adducts, i.e., N(7) adduct of 2'-deoxyguanosine (3), N(1) adduct of 2'-deoxyadenosine (8), N(3) derivative of 2'-deoxyadenosine (9), and N(3) adduct of 2'-deoxycytidine (12), were identified in the hydrolysates by LC/ESI-MS/MS, positive-ion detection mode, 1 H-NMR, and UV, as well as by coelution with the standard samples. The yields of these four adducts in the DNA were calculated based on quant.…”

Section: Experimental Partmentioning

confidence: 99%

“…The presence of 7 (i.e., N(7),N(9)-bis-alkylated guanine) [12] cannot be excluded. Several irrelevant minor adducts derived from reactions of chlorambucil dimers [13] [14] with nucleobases were also detected.…”

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confidence: 99%

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Reactions of 4‐[Bis(2‐chloroethyl)amino]benzenebutanoic Acid (Chlorambucil) with DNA

Florea-Wang

Pawłowicz

Sinkkonen

et al. 2009

Chemistry & Biodiversity

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4-[Bis(2-chloroethyl)amino]benzenebutanoic acid (=chlorambucil, 1; 2.5 mM) was allowed to react with single- and double-stranded calf thymus DNA at physiological pH (cacodylic acid, 50% base) at 37 degrees . The DNA-chlorambucil adducts were identified by analyzing the DNA hydrolysates by NMR, UV, HPLC, LC/ESI-MS/MS techniques as well as by spiking with authentic materials. ssDNA was more reactive than dsDNA, and the order of reactivity in ssDNA was Ade-N1>Gua-N7>Cyt-N3>Ade-N3. The most reactive site in dsDNA was Ade-N3. The Gua-N7 and Ade-N3 adducts were hydrolytically labile. Ade-N7 adduct could not be identified in the hydrolysates of ssDNA or dsDNA. The adduct Gua-N7,N7, which consists of two units of Gua bound together with a unit derived from chlorambucil, is a cross-linking adduct, and it was detected in the hydrolysates of ssDNA and dsDNA. Also several other adducts were detected which could be characterized by spiking with previously isolated authentic adducts or tentatively by MS. The role of chlorambucil-DNA adducts on the cytotoxicity and mutagenity of 1 is also discussed.

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“…3,5−12 The predominant site of DNA alkylation by nitrogen mustards is the N7-atom of guanine residues. 6,8,9 …”

Section: Introductionmentioning

confidence: 99%

Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia-Selective DNA-Oxidizing Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

et al. 2014

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Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells.

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Reactions of N,N-Bis(2-chloroethyl)-p-aminophenylbutyric Acid (Chlorambucil) with 2‘-Deoxyguanosine

Cited by 23 publications

References 23 publications

Reactions of {4‐[Bis(2‐chloroethyl)amino]phenyl}acetic Acid (Phenylacetic Acid Mustard) with 2′‐Deoxyribonucleosides

Reactions of {4‐[Bis(2‐chloroethyl)amino]phenyl}acetic Acid (Phenylacetic Acid Mustard) with 2′‐Deoxyribonucleosides

Reactions of 4‐[Bis(2‐chloroethyl)amino]benzenebutanoic Acid (Chlorambucil) with DNA

Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia-Selective DNA-Oxidizing Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

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