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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

Potentiation of PBD Dimers by Lipophilicity Manipulation

Author(s): Thaїs Cailleau*, Lauren R. Adams, Neha Arora, Gyoung-Dong Kang, Luke Masterson, Neki Patel, John A. Hartley, Shenlan Mao, Jay Harper and Philip W. Howard

Volume 19, Issue 9, 2019

Page: [741 - 752] Pages: 12

DOI: 10.2174/1568026619666190401112517

Price: $65

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.

Keywords: ADC, Pyrrolobenzodiazepine, P-gp pump, Tesirine, N-Methylpiperazine, Amide coupling, Cathepsin B.

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