Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs)

The systematic shortening of the noncovalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate (13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2019-02, Vol.62 (4), p.2127-2139
Main Authors: Corcoran, David B, Lewis, Thomas, Nahar, Kazi S, Jamshidi, Shirin, Fegan, Christopher, Pepper, Chris, Thurston, David E, Rahman, Khondaker Miraz
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Benzodiazepines - chemical synthesis
Benzodiazepines - metabolism
Benzodiazepines - pharmacology
Cell Line, Tumor
DNA - chemistry
DNA - metabolism
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
NF-kappa B - antagonists & inhibitors
NF-kappa B - metabolism
Pyrroles - chemical synthesis
Pyrroles - metabolism
Pyrroles - pharmacology
Quantitative Structure-Activity Relationship
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Summary:The systematic shortening of the noncovalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate (13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the noncovalent element of the molecule on transcription factor inhibitory capacity were also explored through an enzyme-linked immunosorbent assay-based measurement of nuclear NF-κB upon exposure of JJN-3 cells to the synthesized molecules. Although shortening the noncovalent interactive element of 13 had a less than expected effect upon compound cytotoxicity due to reduced DNA interaction, the transcription factor inhibitory capacity of the molecule was notably altered. This study suggests that a relatively short noncovalent side chain at the C8 position of PBD is sufficient to confer cytotoxicity. The shortened PBD monomers provide a new ADC payload scaffold because of their potent cytotoxicity and drug-like properties.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01849