Hedamycin intercalates the DNA helix and, through carbohydrate-mediated recognition in the minor groove, directs N7-alkylation of guanine in the major groove in a sequence-specific manner

Mark Hansen, Sang Yun, Laurence Hurley

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background: The pluramycins are a class of antitumor antibiotics that exert their biological activity through interaction with DNA. Recent studies with the analog altromycin B have determined that these agents intercalate into the DNA molecule, position carbohydrate substituents into both major and minor grooves, and alkylate the DNA molecule by epoxide-mediated electrophilic attack on N7 of guanine located to the 3′ side of the drug molecule. Alkylation is sequence dependent and appears to be modulated by glycoside substituents attached at the corners of a planar chromophore. The altromycin B-like analogs preferentially alkylate 5′AG sequences; hedamycin-like analogs prefer 5′TG and 5′CG sequences. Although the mechanism of guanine modification by altromycin B has been extensively studied, the mechanism of action of hedamycin has not been previously determined. Results: Using high-field NMR, we have shown that hedanrycin stacks to the 5′ side of the guanine nucleotide at the site of intercalation in a DNA decamer, positioning both aminosaccharides into the minor groove to direct alkylation by the epoxide moiety on N7 of guanine. The C10 linked N,N-dimethylvancosamine sugar moiety interacts to the 5′ side of the intercalation site, while the C8 linked anglosamine moiety interacts to the 3′ side. The binding interactions of the two aminosugars steer the C2 double epoxide located in the major groove into the proximity of N7 of guanine. Unexpectedly, it is not the first epoxide that undergoes electrophilic addition to N7 of guanine, which would correspond to altromycin B, but the second, terminal epoxide. Conclusions: We have used two-dimensional NMR to elucidate the sequence-selective recognition of DNA by hedamycin and the mechanism of covalent modification of guanine by this antibiotic. Characterization of the intermolecular interactions between both hedamycin and altromycin B and their targeted DNA sequences has yielded a better understanding of the reasons for variations in sequence selectivity and alkylation reactivity among the pluramycin compounds.

Original languageEnglish (US)
Pages (from-to)229-240
Number of pages12
JournalChemistry and Biology
Volume2
Issue number4
DOIs
StatePublished - 1995
Externally publishedYes

Fingerprint

Alkylation
Guanine
Epoxy Compounds
Carbohydrates
DNA
Intercalation
Molecules
Nuclear magnetic resonance
Anti-Bacterial Agents
Guanine Nucleotides
DNA sequences
Chromophores
Glycosides
Bioactivity
Sugars
hedamycin
altromycin B
Pharmaceutical Preparations

Keywords

  • DNA recognition
  • hedamycin
  • NMR
  • pluramycins

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

Cite this

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title = "Hedamycin intercalates the DNA helix and, through carbohydrate-mediated recognition in the minor groove, directs N7-alkylation of guanine in the major groove in a sequence-specific manner",
abstract = "Background: The pluramycins are a class of antitumor antibiotics that exert their biological activity through interaction with DNA. Recent studies with the analog altromycin B have determined that these agents intercalate into the DNA molecule, position carbohydrate substituents into both major and minor grooves, and alkylate the DNA molecule by epoxide-mediated electrophilic attack on N7 of guanine located to the 3′ side of the drug molecule. Alkylation is sequence dependent and appears to be modulated by glycoside substituents attached at the corners of a planar chromophore. The altromycin B-like analogs preferentially alkylate 5′AG sequences; hedamycin-like analogs prefer 5′TG and 5′CG sequences. Although the mechanism of guanine modification by altromycin B has been extensively studied, the mechanism of action of hedamycin has not been previously determined. Results: Using high-field NMR, we have shown that hedanrycin stacks to the 5′ side of the guanine nucleotide at the site of intercalation in a DNA decamer, positioning both aminosaccharides into the minor groove to direct alkylation by the epoxide moiety on N7 of guanine. The C10 linked N,N-dimethylvancosamine sugar moiety interacts to the 5′ side of the intercalation site, while the C8 linked anglosamine moiety interacts to the 3′ side. The binding interactions of the two aminosugars steer the C2 double epoxide located in the major groove into the proximity of N7 of guanine. Unexpectedly, it is not the first epoxide that undergoes electrophilic addition to N7 of guanine, which would correspond to altromycin B, but the second, terminal epoxide. Conclusions: We have used two-dimensional NMR to elucidate the sequence-selective recognition of DNA by hedamycin and the mechanism of covalent modification of guanine by this antibiotic. Characterization of the intermolecular interactions between both hedamycin and altromycin B and their targeted DNA sequences has yielded a better understanding of the reasons for variations in sequence selectivity and alkylation reactivity among the pluramycin compounds.",
keywords = "DNA recognition, hedamycin, NMR, pluramycins",
author = "Mark Hansen and Sang Yun and Laurence Hurley",
year = "1995",
doi = "10.1016/1074-5521(95)90273-2",
language = "English (US)",
volume = "2",
pages = "229--240",
journal = "Cell Chemical Biology",
issn = "2451-9448",
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T1 - Hedamycin intercalates the DNA helix and, through carbohydrate-mediated recognition in the minor groove, directs N7-alkylation of guanine in the major groove in a sequence-specific manner

AU - Hansen, Mark

AU - Yun, Sang

AU - Hurley, Laurence

PY - 1995

Y1 - 1995

N2 - Background: The pluramycins are a class of antitumor antibiotics that exert their biological activity through interaction with DNA. Recent studies with the analog altromycin B have determined that these agents intercalate into the DNA molecule, position carbohydrate substituents into both major and minor grooves, and alkylate the DNA molecule by epoxide-mediated electrophilic attack on N7 of guanine located to the 3′ side of the drug molecule. Alkylation is sequence dependent and appears to be modulated by glycoside substituents attached at the corners of a planar chromophore. The altromycin B-like analogs preferentially alkylate 5′AG sequences; hedamycin-like analogs prefer 5′TG and 5′CG sequences. Although the mechanism of guanine modification by altromycin B has been extensively studied, the mechanism of action of hedamycin has not been previously determined. Results: Using high-field NMR, we have shown that hedanrycin stacks to the 5′ side of the guanine nucleotide at the site of intercalation in a DNA decamer, positioning both aminosaccharides into the minor groove to direct alkylation by the epoxide moiety on N7 of guanine. The C10 linked N,N-dimethylvancosamine sugar moiety interacts to the 5′ side of the intercalation site, while the C8 linked anglosamine moiety interacts to the 3′ side. The binding interactions of the two aminosugars steer the C2 double epoxide located in the major groove into the proximity of N7 of guanine. Unexpectedly, it is not the first epoxide that undergoes electrophilic addition to N7 of guanine, which would correspond to altromycin B, but the second, terminal epoxide. Conclusions: We have used two-dimensional NMR to elucidate the sequence-selective recognition of DNA by hedamycin and the mechanism of covalent modification of guanine by this antibiotic. Characterization of the intermolecular interactions between both hedamycin and altromycin B and their targeted DNA sequences has yielded a better understanding of the reasons for variations in sequence selectivity and alkylation reactivity among the pluramycin compounds.

AB - Background: The pluramycins are a class of antitumor antibiotics that exert their biological activity through interaction with DNA. Recent studies with the analog altromycin B have determined that these agents intercalate into the DNA molecule, position carbohydrate substituents into both major and minor grooves, and alkylate the DNA molecule by epoxide-mediated electrophilic attack on N7 of guanine located to the 3′ side of the drug molecule. Alkylation is sequence dependent and appears to be modulated by glycoside substituents attached at the corners of a planar chromophore. The altromycin B-like analogs preferentially alkylate 5′AG sequences; hedamycin-like analogs prefer 5′TG and 5′CG sequences. Although the mechanism of guanine modification by altromycin B has been extensively studied, the mechanism of action of hedamycin has not been previously determined. Results: Using high-field NMR, we have shown that hedanrycin stacks to the 5′ side of the guanine nucleotide at the site of intercalation in a DNA decamer, positioning both aminosaccharides into the minor groove to direct alkylation by the epoxide moiety on N7 of guanine. The C10 linked N,N-dimethylvancosamine sugar moiety interacts to the 5′ side of the intercalation site, while the C8 linked anglosamine moiety interacts to the 3′ side. The binding interactions of the two aminosugars steer the C2 double epoxide located in the major groove into the proximity of N7 of guanine. Unexpectedly, it is not the first epoxide that undergoes electrophilic addition to N7 of guanine, which would correspond to altromycin B, but the second, terminal epoxide. Conclusions: We have used two-dimensional NMR to elucidate the sequence-selective recognition of DNA by hedamycin and the mechanism of covalent modification of guanine by this antibiotic. Characterization of the intermolecular interactions between both hedamycin and altromycin B and their targeted DNA sequences has yielded a better understanding of the reasons for variations in sequence selectivity and alkylation reactivity among the pluramycin compounds.

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KW - NMR

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