An optimised synthesis of SG3376, a non-cleavable antibody-drug conjugate pyrrolobenzodiazepine drug-linker

Abstract In recent years, antibody-drug conjugates (ADCs) have been evaluated in a growing number of clinical trials. Preclinical evaluation and the synthetic accessibility of cleavable pyrrolobenzodiazepine drug-linkers, such as talirine and tesirine, have been previously described. This article details how the synthesis of SG3376, a non-cleavable pyrrolobenzodiazepine drug-linker, has been optimised to provide access to late-stage versatile intermediates in a robust and scalable fashion. Of particular importance was the selective deprotection of primary N -Boc in the presence of secondary N -Boc and secondary O- TBS. SG3376 was conjugated to trastuzumab and the resulting ADC was found to have potent cytotoxic activity in a number of HER2-positive cancer cell lines.