Advances in the Study of Pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) Antitumour Antibiotics

Thurston, David E.

doi:10.1007/978-1-349-12356-8_3

Cited by 101 publications

(143 citation statements)

References 65 publications

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“…The PBD series were developed as minor-groove binding covalent molecules. PBDs are antitumor antibiotics derived from Streptomyces species and include anthramycin and tomaymycin (12,13). PBDs interact within the minor groove of DNA by binding covalently to the C2-amino position of a guanine residue.…”

Section: Introductionmentioning

confidence: 99%

“…PBDs interact within the minor groove of DNA by binding covalently to the C2-amino position of a guanine residue. For example, the pyrrolo[2,1-c] [1,4]benzodiazepine dimer SJG-136 (NSC 694501) selectively cross-links guanine residues located on opposite strands of DNA and exhibits potent in vitro cytotoxicity (12). It spans six nucleotides with a preference for binding to purine-GATC-pyrimidine sequences (14).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

Kotecha

Kluza

Wells

et al. 2008

Molecular Cancer Therapeutics

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Many genes involved in cell cycle control have promoters that bind the heterotrimeric transcription factor NF-Y. Several minor-groove binding drugs have been shown to block interactions of transcription factors with cognate DNA-binding sequences. We showed previously that noncovalent minor-groove binding agents block interactions of NF-Y with the promoter of topoisomerase IIA (topo IIA). In this study, we investigated the ability of GWL-78, a pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugate, to inhibit the binding of NF-Y to DNA. Electrophoretic mobility shift assays showed that GWL-78 could displace NF-Y bound to several CCAAT motifs within promoters of genes involved in cell cycle progression. DNase I footprinting of the topo IIA promoter confirmed binding of GWL-78 to AT-rich sequences corresponding to the preferred binding site of NF-Y. Incubation with GWL-78 resulted in displacement of NF-Y binding to DNA. Chromatin immunoprecipitation assays on the topo IIA promoter showed that GWL-78 was able to enter the nucleus and interact with specific DNA sequences. Treatment of NIH3T3 cells with GWL-78 resulted in a block of cell cycle progression, which did not involve activation of p53. Thus, agents such as GWL-78 may be useful in modulating transcription and blocking cellular proliferation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

Kotecha

Kluza

Wells

et al. 2008

Molecular Cancer Therapeutics

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“…KEYWORDS Pyrrolo[2,1-c] [1,4]benzodiazepine (PBD), antitumor agents, GWL-78, DNA, minor-groove binder T he pyrrolo [2,1-c] [1,4]benzodiazepines (PBDs) are a well-known class of sequence-selective covalent-binding DNA-interactive agents [1][2][3][4] that fit perfectly in the minor groove of DNA due to their chiral C11a(S)-position, which provides a right-handed longitudinal twist isohelical with double-stranded DNA. 3 They also possess an electrophilic N10-C11 imine moiety (or the carbinolamine or carbinolamine methyl ether equivalent) that can form a covalent aminal linkage between their C11-position and the nucleophilic C2-NH 2 group of a guanine base.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…3 They also possess an electrophilic N10-C11 imine moiety (or the carbinolamine or carbinolamine methyl ether equivalent) that can form a covalent aminal linkage between their C11-position and the nucleophilic C2-NH 2 group of a guanine base. 3 The simple monomeric PBDs such as the natural products anthramycin ( Figure 1) and tomaymycin typically span three base pairs of DNA. There are numerous reports in the literature based on NMR, 5 X-ray crystallography, 6 molecular modeling, 7 and gelbased experiments (e.g., DNA footprinting 8 and in vitro polymerase stop assays 9 ) suggesting that they have a rank order of preference for binding to 5 0 -Pu-G-Pu-3 0 > Pu-G-Py ∼ Py-G-Pu > Py-G-Py sequences with the adducts oriented so that the PBD A ring points toward the 3 0 terminus of the covalently modified strand.…”

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DNA Sequence Preference and Adduct Orientation of Pyrrolo[2,1-c][1,4]benzodiazepine Antitumor Agents

Rahman

Vassoler

James

et al. 2010

ACS Med. Chem. Lett.

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The pyrrolobenzodiazepines (PBDs) are covalent DNA minor-groove binding agents with a reported preference for binding to 5 0 -Pu-G-Pu sequences with their A rings oriented toward the 3 0 -end of the covalently modified DNA strand. Using HPLC/MS methodology and a range of designed hairpin-forming 17-mer oligonucleotides, the kinetics of reaction of a bis-pyrrole PBD conjugate (GWL-78, 2) has been evaluated with eight isomeric oligonucleotides, each containing a single PBD binding site in one of two locations. The PBD-binding base pair triplets were designed to include every possible combination of A and T bases adjacent to the covalently reacting guanine. Contrary to expectations, 2 reacted most rapidly with TGT and TGA sequences, and adducts were observed to form in both the 3 0 -and the 5 0 -directions. Molecular modeling studies revealed that for 3 0 -oriented adducts, this preference could be explained by formation of a hydrogen bond between the N10-H of the PBD and the oxygen of the C2-carbonyl of a thymine base on the 3 0 -side of the covalently bound guanine. For 5 0 -adducts, an analogous PBD N10-H hydrogen bond may form instead to the N3 of an equivalent adenine on the opposite strand.

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Synthetic Applications of Nitrenium Ions

Wardrop

Bowen

2013

Nitrenes and Nitrenium Ions

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Advances in the Study of Pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) Antitumour Antibiotics

Cited by 101 publications

References 65 publications

Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

DNA Sequence Preference and Adduct Orientation of Pyrrolo[2,1-c][1,4]benzodiazepine Antitumor Agents

Synthetic Applications of Nitrenium Ions

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