Pyrrolo[1,4]benzodiazepine antitumor antibiotics: Evidence for two forms of tomaymycin bound to DNA

Mary D. Barkley, Steve Cheatham, David E. Thurston, Laurence Hurley

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Tomaymycin is an antibiotic belonging to the pyrrolo[1,4]benzodiazepine group of antitumor compounds. Previous studies have shown that tomaymycin and other members of this group, which include anthramycin, sibiromycin, and the neothramycins, bind covalently through N-2 of guanine and lie within the minor groove of DNA. Two fluorescent ground-state species of tomaymycin were observed in protic solvents and on DNA. 1H NMR studies showed that the two fluorescent species in methanol are the 11R,11aS and 115,11aS diastereomeric 11-methyl ethers of tomaymycin. On the basis of epimerization experiments and exchange of carbon-13 from 13CH3OH into the C-11 methoxy group of the tomaymycin methyl ether, a mechanism is proposed for their interconversion via 10,11-anhydrotomaymycin. Coupling information revealed that the solution conformations of the two diastereomers differ, with the C-5 carbonyl lying closer to the plane of the aromatic ring in the 11R, 11aS diastereomer. The fluorescence excitation and emission spectra of the two emitting species in methanol were separated by time-resolved fluorescence spectroscopy and were associated with the diastereomeric forms identified by 1H NMR. Time-resolved fluorescence studies of tomaymycin in protic solvents and on DNA indicated that the absorption spectrum of the longer lifetime component (11R,11aS form) is red-shifted relative to the absorption spectrum of the shorter lifetime component (11S,11aS form), consistent with more extensive conjugation. The two conformational forms of tomaymycin on DNA were tentatively identified as the 11S, 11aS and 11R,11aS diastereomeric adducts, which bind in opposite orientations in the minor groove. This proposal is supported by molecular modeling studies using a 6-mer duplex adduct of d(ATGCAT)2.

Original languageEnglish (US)
Pages (from-to)3021-3031
Number of pages11
JournalBiochemistry
Volume25
Issue number10
StatePublished - 1986
Externally publishedYes

Fingerprint

Anti-Bacterial Agents
DNA
Methyl Ethers
Methanol
Anthramycin
Absorption spectra
Fluorescence
Nuclear magnetic resonance
Molecular modeling
Fluorescence Spectrometry
Fluorescence spectroscopy
Guanine
Bz-423
tomaymycin
Ground state
Conformations
Carbon
Experiments
Proton Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Biochemistry

Cite this

Pyrrolo[1,4]benzodiazepine antitumor antibiotics : Evidence for two forms of tomaymycin bound to DNA. / Barkley, Mary D.; Cheatham, Steve; Thurston, David E.; Hurley, Laurence.

In: Biochemistry, Vol. 25, No. 10, 1986, p. 3021-3031.

Research output: Contribution to journalArticle

Barkley, MD, Cheatham, S, Thurston, DE & Hurley, L 1986, 'Pyrrolo[1,4]benzodiazepine antitumor antibiotics: Evidence for two forms of tomaymycin bound to DNA', Biochemistry, vol. 25, no. 10, pp. 3021-3031.
Barkley, Mary D. ; Cheatham, Steve ; Thurston, David E. ; Hurley, Laurence. / Pyrrolo[1,4]benzodiazepine antitumor antibiotics : Evidence for two forms of tomaymycin bound to DNA. In: Biochemistry. 1986 ; Vol. 25, No. 10. pp. 3021-3031.
@article{2a395bbed7bf46bfaccba08cf27025cb,
title = "Pyrrolo[1,4]benzodiazepine antitumor antibiotics: Evidence for two forms of tomaymycin bound to DNA",
abstract = "Tomaymycin is an antibiotic belonging to the pyrrolo[1,4]benzodiazepine group of antitumor compounds. Previous studies have shown that tomaymycin and other members of this group, which include anthramycin, sibiromycin, and the neothramycins, bind covalently through N-2 of guanine and lie within the minor groove of DNA. Two fluorescent ground-state species of tomaymycin were observed in protic solvents and on DNA. 1H NMR studies showed that the two fluorescent species in methanol are the 11R,11aS and 115,11aS diastereomeric 11-methyl ethers of tomaymycin. On the basis of epimerization experiments and exchange of carbon-13 from 13CH3OH into the C-11 methoxy group of the tomaymycin methyl ether, a mechanism is proposed for their interconversion via 10,11-anhydrotomaymycin. Coupling information revealed that the solution conformations of the two diastereomers differ, with the C-5 carbonyl lying closer to the plane of the aromatic ring in the 11R, 11aS diastereomer. The fluorescence excitation and emission spectra of the two emitting species in methanol were separated by time-resolved fluorescence spectroscopy and were associated with the diastereomeric forms identified by 1H NMR. Time-resolved fluorescence studies of tomaymycin in protic solvents and on DNA indicated that the absorption spectrum of the longer lifetime component (11R,11aS form) is red-shifted relative to the absorption spectrum of the shorter lifetime component (11S,11aS form), consistent with more extensive conjugation. The two conformational forms of tomaymycin on DNA were tentatively identified as the 11S, 11aS and 11R,11aS diastereomeric adducts, which bind in opposite orientations in the minor groove. This proposal is supported by molecular modeling studies using a 6-mer duplex adduct of d(ATGCAT)2.",
author = "Barkley, {Mary D.} and Steve Cheatham and Thurston, {David E.} and Laurence Hurley",
year = "1986",
language = "English (US)",
volume = "25",
pages = "3021--3031",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Pyrrolo[1,4]benzodiazepine antitumor antibiotics

T2 - Evidence for two forms of tomaymycin bound to DNA

AU - Barkley, Mary D.

AU - Cheatham, Steve

AU - Thurston, David E.

AU - Hurley, Laurence

PY - 1986

Y1 - 1986

N2 - Tomaymycin is an antibiotic belonging to the pyrrolo[1,4]benzodiazepine group of antitumor compounds. Previous studies have shown that tomaymycin and other members of this group, which include anthramycin, sibiromycin, and the neothramycins, bind covalently through N-2 of guanine and lie within the minor groove of DNA. Two fluorescent ground-state species of tomaymycin were observed in protic solvents and on DNA. 1H NMR studies showed that the two fluorescent species in methanol are the 11R,11aS and 115,11aS diastereomeric 11-methyl ethers of tomaymycin. On the basis of epimerization experiments and exchange of carbon-13 from 13CH3OH into the C-11 methoxy group of the tomaymycin methyl ether, a mechanism is proposed for their interconversion via 10,11-anhydrotomaymycin. Coupling information revealed that the solution conformations of the two diastereomers differ, with the C-5 carbonyl lying closer to the plane of the aromatic ring in the 11R, 11aS diastereomer. The fluorescence excitation and emission spectra of the two emitting species in methanol were separated by time-resolved fluorescence spectroscopy and were associated with the diastereomeric forms identified by 1H NMR. Time-resolved fluorescence studies of tomaymycin in protic solvents and on DNA indicated that the absorption spectrum of the longer lifetime component (11R,11aS form) is red-shifted relative to the absorption spectrum of the shorter lifetime component (11S,11aS form), consistent with more extensive conjugation. The two conformational forms of tomaymycin on DNA were tentatively identified as the 11S, 11aS and 11R,11aS diastereomeric adducts, which bind in opposite orientations in the minor groove. This proposal is supported by molecular modeling studies using a 6-mer duplex adduct of d(ATGCAT)2.

AB - Tomaymycin is an antibiotic belonging to the pyrrolo[1,4]benzodiazepine group of antitumor compounds. Previous studies have shown that tomaymycin and other members of this group, which include anthramycin, sibiromycin, and the neothramycins, bind covalently through N-2 of guanine and lie within the minor groove of DNA. Two fluorescent ground-state species of tomaymycin were observed in protic solvents and on DNA. 1H NMR studies showed that the two fluorescent species in methanol are the 11R,11aS and 115,11aS diastereomeric 11-methyl ethers of tomaymycin. On the basis of epimerization experiments and exchange of carbon-13 from 13CH3OH into the C-11 methoxy group of the tomaymycin methyl ether, a mechanism is proposed for their interconversion via 10,11-anhydrotomaymycin. Coupling information revealed that the solution conformations of the two diastereomers differ, with the C-5 carbonyl lying closer to the plane of the aromatic ring in the 11R, 11aS diastereomer. The fluorescence excitation and emission spectra of the two emitting species in methanol were separated by time-resolved fluorescence spectroscopy and were associated with the diastereomeric forms identified by 1H NMR. Time-resolved fluorescence studies of tomaymycin in protic solvents and on DNA indicated that the absorption spectrum of the longer lifetime component (11R,11aS form) is red-shifted relative to the absorption spectrum of the shorter lifetime component (11S,11aS form), consistent with more extensive conjugation. The two conformational forms of tomaymycin on DNA were tentatively identified as the 11S, 11aS and 11R,11aS diastereomeric adducts, which bind in opposite orientations in the minor groove. This proposal is supported by molecular modeling studies using a 6-mer duplex adduct of d(ATGCAT)2.

UR - http://www.scopus.com/inward/record.url?scp=0022458567&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0022458567&partnerID=8YFLogxK

M3 - Article

C2 - 3718937

AN - SCOPUS:0022458567

VL - 25

SP - 3021

EP - 3031

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 10

ER -