title: Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin.
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.
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Kemp
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK. Electronic address: tiberghiena@medimmune.com.
authors.forename: Arnaud C
authors.initials: AC
authors.lastname: Tiberghien
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: Neki V
authors.initials: NV
authors.lastname: Patel
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: Francois
authors.initials: F
authors.lastname: D'Hooge
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Nilapwar
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Adams
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Corbett
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Williams
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.affiliation: Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK. Electronic address: Philip.Howard@spirogen.com.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D001569:Benzodiazepines / Q000737:chemistry*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry*; D066298:In Vitro Techniques
chemical_list: D000617:Aminoglycosides; D000970:Antineoplastic Agents; D018796:Immunoconjugates; C100298:sibiromycin; D001569:Benzodiazepines
keywords: Antibody-drug conjugate; DNA minor groove binding agent; Pyrrolobenzodiazepine dimer; SG3227; Sibiromycin