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

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posted on 2023-06-09, 17:04 authored by David B Corcoran, Thomas Lewis, Kazi S Nahar, Shirin Jamshidi, Christopher Fegan, Christopher PepperChristopher Pepper, David E Thurston, Khondaker Miraz Rahman
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-?B 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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society

Issue

4

Volume

62

Page range

2127-2139

Department affiliated with

  • Clinical and Experimental Medicine Publications

Research groups affiliated with

  • Haematology Research Group Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-02-28

First Open Access (FOA) Date

2019-02-28

First Compliant Deposit (FCD) Date

2019-02-28

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