Effects of systematic shortening of noncovalent C8 side chain on the cytotoxicity and NF-κB inhibitory capacity of pyrrolobenzodiazepines (PBDs)

Corcoran, David B, Lewis, Thomas, Nahar, Kazi S, Jamshidi, Shirin, Fegan, Christopher, Pepper, Chris, Thurston, David E and Rahman, Khondaker Miraz (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). pp. 2127-2139. ISSN 0022-2623

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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 druglike properties.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Research Centres and Groups: Haematology Research Group
Subjects: R Medicine
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Depositing User: Gemma Hamilton
Date Deposited: 28 Feb 2019 10:30
Last Modified: 01 Jul 2019 14:01
URI: http://sro.sussex.ac.uk/id/eprint/82253

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