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Formation of a Novel C11-Acetone Adduct of a Pyrrolobenzodiazepine (PBD) with Loss of Cytotoxicity

Research output: Contribution to journalLetter

Original languageEnglish
Pages (from-to)1112-1116
Number of pages5
JournalSYNLETT
Volume29
Issue number8
Early online date10 Apr 2018
DOIs
Publication statusE-pub ahead of print - 10 Apr 2018

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Abstract

The pyrrolidine-catalysed formation of novel diastereomeric C11-acetone adducts was observed during the chromatographic purification of pyrrolobenzodiazepine (PBD) compounds in the presence of acetone. The mechanism of this reaction was explored and the adducts obtained fully characterised. Talirine, the cytotoxic payload element of the antibody-drug conjugate (ADC) vadastuximab talirine, was also found to form a bis-adduct under similar conditions. A cellular cytotoxicity evaluation of the modified PBD compounds confirmed their lack of cytotoxicity, consistent with loss of the DNA-interactive N10–C11 imine functionality. As well as the new chemistry reported here, given the number of PBD-based ADCs presently in the clinic, this observation may be important for the larger-scale manufacture of PBD-based products.

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