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

David Corcoran; Thomas  Lewis; Kazi Sharmin Nahar; Shirin Jamshidi; Christopher  Fegan; Chris Pepper; David Edwin Thurston; Khondaker Mirazur Rahman

doi:10.1021/acs.jmedchem.8b01849

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

David Corcoran, Thomas Lewis, Kazi Sharmin Nahar, Shirin Jamshidi, Christopher Fegan, Chris Pepper, David Edwin Thurston, Khondaker Mirazur Rahman

Institute of Pharmaceutical Science

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

17 Citations (Scopus)

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Abstract

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.

Original language	English
Article number	8b01849
Pages (from-to)	2127-2139
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	4
Early online date	27 Nov 2018
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01849
Publication status	Published - 28 Feb 2019

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10.1021/acs.jmedchem.8b01849Licence: CC BY

Effects of Systematic Shortening_CORCORAN_Published Online 27 November 2019_GOLD VoR (CC BY)Final published version, 2.58 MBLicence: CC BY

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Corcoran, D., Lewis, T., Nahar, K. S., Jamshidi, S., Fegan, C., Pepper, C., Thurston, D. E., & Rahman, K. M. (2019). Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs). Journal of Medicinal Chemistry, 62(4), 2127-2139. Article 8b01849. https://doi.org/10.1021/acs.jmedchem.8b01849

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abstract = "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.",

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AU - Nahar, Kazi Sharmin

AU - Jamshidi, Shirin

AU - Fegan, Christopher

AU - Pepper, Chris

AU - Thurston, David Edwin

AU - Rahman, Khondaker Mirazur

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AB - 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.

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

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