Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA

Mohammad A. Basher; Khondaker Miraz Rahman; Paul J.M. Jackson; David E. Thurston; Keith R. Fox

doi:10.1016/j.bpc.2017.08.006

Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA

Mohammad A. Basher
, Khondaker Miraz Rahman
, Paul J.M. Jackson
, David E. Thurston
, Keith R. Fox

Institute of Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

118 Downloads (Pure)

Abstract

DNA footprinting and melting experiments have been used to examine the sequence-specific binding of C8-conjugates of pyrrolobenzodiazepines (PBDs) and benzofused rings including benzothiophene and benzofuran, which are attached using pyrrole- or imidazole-containing linkers. The conjugates modulate the covalent attachment points of the PBDs, so that they bind best to guanines flanked by A/T-rich sequences on either the 5′- or 3′-side. The linker affects the binding, and pyrrole produces larger changes than imidazole. Melting studies with 14-mer oligonucleotide duplexes confirm covalent attachment of the conjugates, which show a different selectivity to anthramycin and reveal that more than one ligand molecule can bind to each duplex.

Original language	English
Pages (from-to)	53-61
Journal	Biophysical Chemistry
Volume	230
Early online date	1 Sept 2017
DOIs	https://doi.org/10.1016/j.bpc.2017.08.006
Publication status	Published - Nov 2017

Keywords

Conjugate
Anthramycin
PBD
Polyamide
Footprinting
DNA melting

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10.1016/j.bpc.2017.08.006

Sequence-selective binding_BASHER_Publishedonline1September2017_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 1.85 MBLicence: CC BY-NC-ND

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title = "Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA",

abstract = "DNA footprinting and melting experiments have been used to examine the sequence-specific binding of C8-conjugates of pyrrolobenzodiazepines (PBDs) and benzofused rings including benzothiophene and benzofuran, which are attached using pyrrole- or imidazole-containing linkers. The conjugates modulate the covalent attachment points of the PBDs, so that they bind best to guanines flanked by A/T-rich sequences on either the 5′- or 3′-side. The linker affects the binding, and pyrrole produces larger changes than imidazole. Melting studies with 14-mer oligonucleotide duplexes confirm covalent attachment of the conjugates, which show a different selectivity to anthramycin and reveal that more than one ligand molecule can bind to each duplex.",

keywords = "Conjugate, Anthramycin, PBD, Polyamide, Footprinting, DNA melting",

author = "Basher, \{Mohammad A.\} and Rahman, \{Khondaker Miraz\} and Jackson, \{Paul J.M.\} and Thurston, \{David E.\} and Fox, \{Keith R.\}",

year = "2017",

month = nov,

doi = "10.1016/j.bpc.2017.08.006",

language = "English",

volume = "230",

pages = "53--61",

journal = "Biophysical Chemistry",

issn = "0301-4622",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA

AU - Basher, Mohammad A.

AU - Rahman, Khondaker Miraz

AU - Jackson, Paul J.M.

AU - Thurston, David E.

AU - Fox, Keith R.

PY - 2017/11

Y1 - 2017/11

N2 - DNA footprinting and melting experiments have been used to examine the sequence-specific binding of C8-conjugates of pyrrolobenzodiazepines (PBDs) and benzofused rings including benzothiophene and benzofuran, which are attached using pyrrole- or imidazole-containing linkers. The conjugates modulate the covalent attachment points of the PBDs, so that they bind best to guanines flanked by A/T-rich sequences on either the 5′- or 3′-side. The linker affects the binding, and pyrrole produces larger changes than imidazole. Melting studies with 14-mer oligonucleotide duplexes confirm covalent attachment of the conjugates, which show a different selectivity to anthramycin and reveal that more than one ligand molecule can bind to each duplex.

AB - DNA footprinting and melting experiments have been used to examine the sequence-specific binding of C8-conjugates of pyrrolobenzodiazepines (PBDs) and benzofused rings including benzothiophene and benzofuran, which are attached using pyrrole- or imidazole-containing linkers. The conjugates modulate the covalent attachment points of the PBDs, so that they bind best to guanines flanked by A/T-rich sequences on either the 5′- or 3′-side. The linker affects the binding, and pyrrole produces larger changes than imidazole. Melting studies with 14-mer oligonucleotide duplexes confirm covalent attachment of the conjugates, which show a different selectivity to anthramycin and reveal that more than one ligand molecule can bind to each duplex.

KW - Conjugate

KW - Anthramycin

KW - PBD

KW - Polyamide

KW - Footprinting

KW - DNA melting

U2 - 10.1016/j.bpc.2017.08.006

DO - 10.1016/j.bpc.2017.08.006

M3 - Article

SN - 0301-4622

VL - 230

SP - 53

EP - 61

JO - Biophysical Chemistry

JF - Biophysical Chemistry

ER -

Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA

Abstract

Keywords

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