Pyrrolo(1,4)benzodiazepine antitumor antibiotics In vitro interaction of anthramycin, sibiromycin and tomaymycin with DNA using specifically radiolabelled molecules

Laurence Hurley, Chandrachuranand Gairola, Milton Zmijewski

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55 Citations (Scopus)

Abstract

Anthramycin, tomaymycin and sibiromycin are pyrrolo(1,4)benzodiazepine antitumor antibiotics. These compounds react with DNA and other guanine-containing polydeoxynucleotides to form covalently bound antibiotic · polydeoxynucleotide complexes. Experiments utilizing radiolabelled antibiotics have led to the following conclusions: 1. 1. Sibiromycin reacts much faster than either anthramycin or tomaymycin with DNA. 2. 2. At saturation binding the final antibiotic to base ratios for sibiromycin, anthramycin and tomaymycin are 1 : 8.8, 1 : 12.9, and 1 : 18.2 respectively. 3. 3. No reaction with RNA or protein occurs with the pyrrolo(1,4)benzodiazepine antibiotics. 4. 4. Sibiromycin effectively competes for the same DNA binding sites as anthramycin and tomaymycin; however, there is only partial overlap for the same binding sites between anthramycin and tomaymycin. 5. 5. Whereas all three pyrrolo(1,4)benzodiazepine antibiotic · DNA complexes are relatively stable to alkaline conditions, their stability under acidic conditions increases in the order tomaymycin, anthramycin and sibiromycin. 6. 6. No loss of non-exchangeable hydrogens in either the pyrrol ring or the side chains of these antibiotics occurs upon formation of their complexes with DNA. 7. 7. Unchanged antibiotic has been demonstrated to be released upon acid treatment of the anthramycin · DNA and tomaymycin · DNA complexes. 8. 8. A Schiffbase linkage between the antibiotics and DNA has been eliminated. The comparative reactivity of the three antibiotics towards DNA and the stability of their DNA complexes is discussed in relation to their structures. A working hypothesis for the formation of the antibiotic · DNA covalent complexes is proposed based upon the available information.

Original languageEnglish (US)
Pages (from-to)521-535
Number of pages15
JournalBBA Section Nucleic Acids And Protein Synthesis
Volume475
Issue number3
DOIs
StatePublished - Apr 4 1977
Externally publishedYes

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Anthramycin
Anti-Bacterial Agents
DNA
tomaymycin
sibiromycin
Bz-423
In Vitro Techniques
Binding Sites
Base Composition
Guanine

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "Pyrrolo(1,4)benzodiazepine antitumor antibiotics In vitro interaction of anthramycin, sibiromycin and tomaymycin with DNA using specifically radiolabelled molecules",
abstract = "Anthramycin, tomaymycin and sibiromycin are pyrrolo(1,4)benzodiazepine antitumor antibiotics. These compounds react with DNA and other guanine-containing polydeoxynucleotides to form covalently bound antibiotic · polydeoxynucleotide complexes. Experiments utilizing radiolabelled antibiotics have led to the following conclusions: 1. 1. Sibiromycin reacts much faster than either anthramycin or tomaymycin with DNA. 2. 2. At saturation binding the final antibiotic to base ratios for sibiromycin, anthramycin and tomaymycin are 1 : 8.8, 1 : 12.9, and 1 : 18.2 respectively. 3. 3. No reaction with RNA or protein occurs with the pyrrolo(1,4)benzodiazepine antibiotics. 4. 4. Sibiromycin effectively competes for the same DNA binding sites as anthramycin and tomaymycin; however, there is only partial overlap for the same binding sites between anthramycin and tomaymycin. 5. 5. Whereas all three pyrrolo(1,4)benzodiazepine antibiotic · DNA complexes are relatively stable to alkaline conditions, their stability under acidic conditions increases in the order tomaymycin, anthramycin and sibiromycin. 6. 6. No loss of non-exchangeable hydrogens in either the pyrrol ring or the side chains of these antibiotics occurs upon formation of their complexes with DNA. 7. 7. Unchanged antibiotic has been demonstrated to be released upon acid treatment of the anthramycin · DNA and tomaymycin · DNA complexes. 8. 8. A Schiffbase linkage between the antibiotics and DNA has been eliminated. The comparative reactivity of the three antibiotics towards DNA and the stability of their DNA complexes is discussed in relation to their structures. A working hypothesis for the formation of the antibiotic · DNA covalent complexes is proposed based upon the available information.",
author = "Laurence Hurley and Chandrachuranand Gairola and Milton Zmijewski",
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T1 - Pyrrolo(1,4)benzodiazepine antitumor antibiotics In vitro interaction of anthramycin, sibiromycin and tomaymycin with DNA using specifically radiolabelled molecules

AU - Hurley, Laurence

AU - Gairola, Chandrachuranand

AU - Zmijewski, Milton

PY - 1977/4/4

Y1 - 1977/4/4

N2 - Anthramycin, tomaymycin and sibiromycin are pyrrolo(1,4)benzodiazepine antitumor antibiotics. These compounds react with DNA and other guanine-containing polydeoxynucleotides to form covalently bound antibiotic · polydeoxynucleotide complexes. Experiments utilizing radiolabelled antibiotics have led to the following conclusions: 1. 1. Sibiromycin reacts much faster than either anthramycin or tomaymycin with DNA. 2. 2. At saturation binding the final antibiotic to base ratios for sibiromycin, anthramycin and tomaymycin are 1 : 8.8, 1 : 12.9, and 1 : 18.2 respectively. 3. 3. No reaction with RNA or protein occurs with the pyrrolo(1,4)benzodiazepine antibiotics. 4. 4. Sibiromycin effectively competes for the same DNA binding sites as anthramycin and tomaymycin; however, there is only partial overlap for the same binding sites between anthramycin and tomaymycin. 5. 5. Whereas all three pyrrolo(1,4)benzodiazepine antibiotic · DNA complexes are relatively stable to alkaline conditions, their stability under acidic conditions increases in the order tomaymycin, anthramycin and sibiromycin. 6. 6. No loss of non-exchangeable hydrogens in either the pyrrol ring or the side chains of these antibiotics occurs upon formation of their complexes with DNA. 7. 7. Unchanged antibiotic has been demonstrated to be released upon acid treatment of the anthramycin · DNA and tomaymycin · DNA complexes. 8. 8. A Schiffbase linkage between the antibiotics and DNA has been eliminated. The comparative reactivity of the three antibiotics towards DNA and the stability of their DNA complexes is discussed in relation to their structures. A working hypothesis for the formation of the antibiotic · DNA covalent complexes is proposed based upon the available information.

AB - Anthramycin, tomaymycin and sibiromycin are pyrrolo(1,4)benzodiazepine antitumor antibiotics. These compounds react with DNA and other guanine-containing polydeoxynucleotides to form covalently bound antibiotic · polydeoxynucleotide complexes. Experiments utilizing radiolabelled antibiotics have led to the following conclusions: 1. 1. Sibiromycin reacts much faster than either anthramycin or tomaymycin with DNA. 2. 2. At saturation binding the final antibiotic to base ratios for sibiromycin, anthramycin and tomaymycin are 1 : 8.8, 1 : 12.9, and 1 : 18.2 respectively. 3. 3. No reaction with RNA or protein occurs with the pyrrolo(1,4)benzodiazepine antibiotics. 4. 4. Sibiromycin effectively competes for the same DNA binding sites as anthramycin and tomaymycin; however, there is only partial overlap for the same binding sites between anthramycin and tomaymycin. 5. 5. Whereas all three pyrrolo(1,4)benzodiazepine antibiotic · DNA complexes are relatively stable to alkaline conditions, their stability under acidic conditions increases in the order tomaymycin, anthramycin and sibiromycin. 6. 6. No loss of non-exchangeable hydrogens in either the pyrrol ring or the side chains of these antibiotics occurs upon formation of their complexes with DNA. 7. 7. Unchanged antibiotic has been demonstrated to be released upon acid treatment of the anthramycin · DNA and tomaymycin · DNA complexes. 8. 8. A Schiffbase linkage between the antibiotics and DNA has been eliminated. The comparative reactivity of the three antibiotics towards DNA and the stability of their DNA complexes is discussed in relation to their structures. A working hypothesis for the formation of the antibiotic · DNA covalent complexes is proposed based upon the available information.

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