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

David Corcoran; Pietro Picconi; Connie Kin Fun Chui; George Procopiou; Ilona Pysz; Khondaker Mirazur Rahman; David Edwin Thurston

doi:10.1055/s-0036-1591552

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

David Corcoran, Pietro Picconi, Connie Kin Fun Chui, George Procopiou, Ilona Pysz, Khondaker Mirazur Rahman, David Edwin Thurston

Institute of Pharmaceutical Science

Femtogenix Limited

Research output: Contribution to journal › Letter › peer-review

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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.

Original language	English
Pages (from-to)	1112-1116
Number of pages	5
Journal	SYNLETT
Volume	29
Issue number	8
Early online date	10 Apr 2018
DOIs	https://doi.org/10.1055/s-0036-1591552
Publication status	E-pub ahead of print - 10 Apr 2018

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title = "Formation of a Novel C11-Acetone Adduct of a Pyrrolobenzodiazepine (PBD) with Loss of Cytotoxicity",

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.",

author = "David Corcoran and Pietro Picconi and Chui, {Connie Kin Fun} and George Procopiou and Ilona Pysz and Rahman, {Khondaker Mirazur} and Thurston, {David Edwin}",

year = "2018",

month = apr,

day = "10",

doi = "10.1055/s-0036-1591552",

language = "English",

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journal = "SYNLETT",

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T1 - Formation of a Novel C11-Acetone Adduct of a Pyrrolobenzodiazepine (PBD) with Loss of Cytotoxicity

AU - Corcoran, David

AU - Picconi, Pietro

AU - Chui, Connie Kin Fun

AU - Procopiou, George

AU - Pysz, Ilona

AU - Rahman, Khondaker Mirazur

AU - Thurston, David Edwin

PY - 2018/4/10

Y1 - 2018/4/10

N2 - 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.

AB - 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.

U2 - 10.1055/s-0036-1591552

DO - 10.1055/s-0036-1591552

M3 - Letter

SN - 0936-5214

VL - 29

SP - 1112

EP - 1116

JO - SYNLETT

JF - SYNLETT

IS - 8

ER -

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

Abstract

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