Alkylation of N2 in deoxyguanosine by dehydroretronecine, a carcinogenic metabolite of the pyrrolizidine alkaloid monocrotaline

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Abstract

Dehydroretronecine, an antimitotic and carcinogenic agent, reacted with deoxyguanosine at pH 7.4 in vitro to yield in nearly equal quantities two major adducts, which were isolated by thin-layer and high-pressure liquid chromatography. The adducts were stable at pH 8.7 and 30° for at least 24 hr, showed pK(a)s at acidic and alkaline pHs, reacted with 4-(p-nitrobenzyl)-pyridine, had a nonexchangeable guan-8-yl proton, and contained equimolar quantities of the pyrrole and nucleoside moieties. From the above data and comparison of proton magnetic resonance spectra of dehydroretronecine, deoxyguanosine, and the adducts, both products were identified as derivatives with a bond between C-7 of dehydrosupinidine and N2 of deoxyguanosine. Mass spectral fragmentation patterns and infrared and ultraviolet absorbance spectra were also consistent with N2 substitution. Circular dichroism spectra established the identities of each of the adducts as 7-(deoxyguanosin-N2-yl)dehydrosupinidine; they are enantiomeric at C-7. These results demonstrate that the reactive electrophile derived from protonated dehydroretronecine readily alkylates the N2 position of deoxyguanosine at C-7 in an S(N)1 reaction to yield a racemic mixture of products.

Original languageEnglish (US)
Pages (from-to)8-14
Number of pages7
JournalCancer Research
Volume42
Issue number1
StatePublished - 1982
Externally publishedYes

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Monocrotaline
Pyrrolizidine Alkaloids
Deoxyguanosine
Alkylation
Protons
Antimitotic Agents
Pyrroles
Circular Dichroism
Nucleosides
Magnetic Resonance Spectroscopy
High Pressure Liquid Chromatography
dehydroretronecine
dehydrosupinidine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "Alkylation of N2 in deoxyguanosine by dehydroretronecine, a carcinogenic metabolite of the pyrrolizidine alkaloid monocrotaline",
abstract = "Dehydroretronecine, an antimitotic and carcinogenic agent, reacted with deoxyguanosine at pH 7.4 in vitro to yield in nearly equal quantities two major adducts, which were isolated by thin-layer and high-pressure liquid chromatography. The adducts were stable at pH 8.7 and 30° for at least 24 hr, showed pK(a)s at acidic and alkaline pHs, reacted with 4-(p-nitrobenzyl)-pyridine, had a nonexchangeable guan-8-yl proton, and contained equimolar quantities of the pyrrole and nucleoside moieties. From the above data and comparison of proton magnetic resonance spectra of dehydroretronecine, deoxyguanosine, and the adducts, both products were identified as derivatives with a bond between C-7 of dehydrosupinidine and N2 of deoxyguanosine. Mass spectral fragmentation patterns and infrared and ultraviolet absorbance spectra were also consistent with N2 substitution. Circular dichroism spectra established the identities of each of the adducts as 7-(deoxyguanosin-N2-yl)dehydrosupinidine; they are enantiomeric at C-7. These results demonstrate that the reactive electrophile derived from protonated dehydroretronecine readily alkylates the N2 position of deoxyguanosine at C-7 in an S(N)1 reaction to yield a racemic mixture of products.",
author = "Kent Robertson",
year = "1982",
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journal = "Journal of Cancer Research",
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T1 - Alkylation of N2 in deoxyguanosine by dehydroretronecine, a carcinogenic metabolite of the pyrrolizidine alkaloid monocrotaline

AU - Robertson, Kent

PY - 1982

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N2 - Dehydroretronecine, an antimitotic and carcinogenic agent, reacted with deoxyguanosine at pH 7.4 in vitro to yield in nearly equal quantities two major adducts, which were isolated by thin-layer and high-pressure liquid chromatography. The adducts were stable at pH 8.7 and 30° for at least 24 hr, showed pK(a)s at acidic and alkaline pHs, reacted with 4-(p-nitrobenzyl)-pyridine, had a nonexchangeable guan-8-yl proton, and contained equimolar quantities of the pyrrole and nucleoside moieties. From the above data and comparison of proton magnetic resonance spectra of dehydroretronecine, deoxyguanosine, and the adducts, both products were identified as derivatives with a bond between C-7 of dehydrosupinidine and N2 of deoxyguanosine. Mass spectral fragmentation patterns and infrared and ultraviolet absorbance spectra were also consistent with N2 substitution. Circular dichroism spectra established the identities of each of the adducts as 7-(deoxyguanosin-N2-yl)dehydrosupinidine; they are enantiomeric at C-7. These results demonstrate that the reactive electrophile derived from protonated dehydroretronecine readily alkylates the N2 position of deoxyguanosine at C-7 in an S(N)1 reaction to yield a racemic mixture of products.

AB - Dehydroretronecine, an antimitotic and carcinogenic agent, reacted with deoxyguanosine at pH 7.4 in vitro to yield in nearly equal quantities two major adducts, which were isolated by thin-layer and high-pressure liquid chromatography. The adducts were stable at pH 8.7 and 30° for at least 24 hr, showed pK(a)s at acidic and alkaline pHs, reacted with 4-(p-nitrobenzyl)-pyridine, had a nonexchangeable guan-8-yl proton, and contained equimolar quantities of the pyrrole and nucleoside moieties. From the above data and comparison of proton magnetic resonance spectra of dehydroretronecine, deoxyguanosine, and the adducts, both products were identified as derivatives with a bond between C-7 of dehydrosupinidine and N2 of deoxyguanosine. Mass spectral fragmentation patterns and infrared and ultraviolet absorbance spectra were also consistent with N2 substitution. Circular dichroism spectra established the identities of each of the adducts as 7-(deoxyguanosin-N2-yl)dehydrosupinidine; they are enantiomeric at C-7. These results demonstrate that the reactive electrophile derived from protonated dehydroretronecine readily alkylates the N2 position of deoxyguanosine at C-7 in an S(N)1 reaction to yield a racemic mixture of products.

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