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Potentiation of PBD Dimers by Lipophilicity Manipulation

Cailleau, T; Adams, LR; Arora, N; Kang, G-D; Masterson, L; Patel, N; Hartley, JA; ... Howard, PW; + view all (2019) Potentiation of PBD Dimers by Lipophilicity Manipulation. Current Topics in Medicinal Chemistry , 19 (9) pp. 741-752. 10.2174/1568026619666190401112517. Green open access

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Abstract

Background & Introduction: Pyrrolobenzodiazepine (PBD) dimers are highly potent DNA cross-linking agents used as warheads in Antibody Drug Conjugates (ADCs) for cancer therapy. We propose to investigate the correlation existing between the lipophilicity of those molecules and their activity (both in vitro and in vivo) as well as any effect observed during conjugation. / Materials and Methods: Reaction progress was monitored by Thin-Layer Chromatography (TLC) using Merck Kieselgel 60 F254 silica gel, with a fluorescent indicator on aluminium plates. Visualisation of TLC was achieved with UV light or iodine vapour unless otherwise stated. Flash chromatography was performed using Merck Kieselgel 60 F254 silica gel. / Results: We have successfully designed and synthesized a novel PBD warhead (SG3312) with enhanced physicochemical properties. The warhead also displayed increased potency in vitro. After overcoming some epimerization issues, the synthesis of enantiomerically pure payload was achieved (SG3259) and fulfilled our criteria for a simplified and more efficient conjugation. No addition of propylene glycol was required, and high DAR and excellent monomeric purity were achieved. / Conclusion: The ADC (Herceptin-maia-SG3259) has been shown to release the active warhead (SG3312) upon exposure to Cathepsin B and demonstrated encouraging activity both in vitro and in vivo.

Type: Article
Title: Potentiation of PBD Dimers by Lipophilicity Manipulation
Location: United Arab Emirates
Open access status: An open access version is available from UCL Discovery
DOI: 10.2174/1568026619666190401112517
Publisher version: https://doi.org/10.2174/1568026619666190401112517
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: ADC, Pyrrolobenzodiazepine, P-gp pump, Tesirine, N-Methylpiperazine, Amide coupling, Cathepsin B
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10112596
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