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Observation of a single-stranded DNA/pyrrolobenzodiazepine adduct.

Pyrrolobenzodiazepine (PBD) antitumor agents have, to date, only been observed to bind to duplex DNA, apparently requiring a minor groove environment for covalent bond formation between their C11-position and the C2-NH(2) functionality of a guanine base. Using an HPLC/MS assay we have now observed a... Full description

Journal Title: Journal of the American Chemical Society December 7, 2011, Vol.133(48), pp.19376-19385
Main Author: Rahman, Khondaker M
Other Authors: James, Colin H , Bui, Tam T T , Drake, Alex F , Thurston, David E
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja205395r
Link: http://search.proquest.com/docview/907145712/?pq-origsite=primo
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title: Observation of a single-stranded DNA/pyrrolobenzodiazepine adduct.
format: Article
creator:
  • Rahman, Khondaker M
  • James, Colin H
  • Bui, Tam T T
  • Drake, Alex F
  • Thurston, David E
subjects:
  • Antineoplastic Agents–Analysis
  • Base Sequence–Pharmacology
  • Benzodiazepines–Analysis
  • DNA Adducts–Pharmacology
  • DNA, Single-Stranded–Analysis
  • Models, Molecular–Metabolism
  • Nucleic Acid Conformation–Chemistry
  • Pyrroles–Metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization–Drug Effects
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization–Analysis
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization–Pharmacology
  • Antineoplastic Agents
  • DNA Adducts
  • DNA, Single-Stranded
  • Pyrroles
  • Pyrrolo(2,1-C)(1,4)Benzodiazepine
  • Benzodiazepines
ispartof: Journal of the American Chemical Society, December 7, 2011, Vol.133(48), pp.19376-19385
description: Pyrrolobenzodiazepine (PBD) antitumor agents have, to date, only been observed to bind to duplex DNA, apparently requiring a minor groove environment for covalent bond formation between their C11-position and the C2-NH(2) functionality of a guanine base. Using an HPLC/MS assay we have now observed and isolated for the first time PBD adducts with single-stranded DNA fragments. Surprisingly, these adducts could only be formed through dissociation of duplex DNA adducts and not by direct interaction of PBDs with single-stranded DNA. They were sufficiently stable for characterization by MALDI-TOF-MS and remained intact after storing at -20 °C for at least 20 days, although the PBD became detached from the DNA within 7 days if stored at room temperature. Furthermore, addition of a complementary strand allowed the duplex adduct to reform. The relative stability of single-stranded PBD/DNA adducts despite a complete loss of minor groove structure was further confirmed by CD spectroscopic analysis. The CD signal induced by the presence of a PBD molecule in the single-stranded adducts remained prominent despite heating for 2 h at 50-60 °C, thus indicating their relatively robust nature.
language: eng
source:
identifier: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja205395r
fulltext: no_fulltext
issn:
  • 15205126
  • 1520-5126
url: Link


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titleObservation of a single-stranded DNA/pyrrolobenzodiazepine adduct.
creatorRahman, Khondaker M ; James, Colin H ; Bui, Tam T T ; Drake, Alex F ; Thurston, David E
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subjectAntineoplastic Agents–Analysis ; Base Sequence–Pharmacology ; Benzodiazepines–Analysis ; DNA Adducts–Pharmacology ; DNA, Single-Stranded–Analysis ; Models, Molecular–Metabolism ; Nucleic Acid Conformation–Chemistry ; Pyrroles–Metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization–Drug Effects ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization–Analysis ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization–Pharmacology ; Antineoplastic Agents ; DNA Adducts ; DNA, Single-Stranded ; Pyrroles ; Pyrrolo(2,1-C)(1,4)Benzodiazepine ; Benzodiazepines
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descriptionPyrrolobenzodiazepine (PBD) antitumor agents have, to date, only been observed to bind to duplex DNA, apparently requiring a minor groove environment for covalent bond formation between their C11-position and the C2-NH(2) functionality of a guanine base. Using an HPLC/MS assay we have now observed and isolated for the first time PBD adducts with single-stranded DNA fragments. Surprisingly, these adducts could only be formed through dissociation of duplex DNA adducts and not by direct interaction of PBDs with single-stranded DNA. They were sufficiently stable for characterization by MALDI-TOF-MS and remained intact after storing at -20 °C for at least 20 days, although the PBD became detached from the DNA within 7 days if stored at room temperature. Furthermore, addition of a complementary strand allowed the duplex adduct to reform. The relative stability of single-stranded PBD/DNA adducts despite a complete loss of minor groove structure was further confirmed by CD spectroscopic analysis. The CD signal induced by the presence of a PBD molecule in the single-stranded adducts remained prominent despite heating for 2 h at 50-60 °C, thus indicating their relatively robust nature.
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