Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin. Issue 5 (1st March 2017)

• Record Type: Journal Article
• Authors: Kemp, Gary C.; Tiberghien, Arnaud C.; Patel, Neki V.; D'Hooge, Francois; Nilapwar, Sanjay M.; Adams, Lauren R.; Corbett, Simon; Williams, David G.; Hartley, John A.; Howard, Philip W.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 5(2017)
• Page Start: 1154
• Page End: 1158
• Publication Date: 2017-03-01
• Subjects: SG3227 -- Antibody-drug conjugate -- Sibiromycin -- Pyrrolobenzodiazepine dimer -- DNA minor groove binding agent; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.01.074
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A novel pyrrolobenzodiazepine dimer payload, SG3227, was rationally designed based on the naturally occurring antitumour compound sibiromycin. SG3227 was synthesized from a dimeric core in an efficient fashion. An unexpected room temperature Diels-Alder reaction occurred during the final step of the synthesis and was circumvented by use of an iodoacetamide conjugation moiety in place of a maleimide. The payload was successfully conjugated to trastuzumab and the resulting ADC exhibited potent activity against a HER2-expressing human cancer cell line in vitro .