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Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin.

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.

Bioorg Med Chem Lett ; 27(5): 1154-1158, 2017 03 01.

Artículo en Inglés | MEDLINE | ID: mdl-28188066

RESUMEN

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.

Asunto(s)

Aminoglicósidos/química , Antineoplásicos/química , Benzodiazepinas/química , Inmunoconjugados/química , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro

RESUMEN

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