Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine–Anthracenecarboxyimide as a Payload for Antibody–Drug Conjugate

Abstract

A novel series of hybrid molecules combining pyrrolobenzodiazepine (PBD) and anthracenecarboxyimide pharmacophores were designed, synthesized, and tested for <i>in vitro</i> cytotoxicity against various cancer cell lines. The most potent compound from this series, <b>37b3</b>, exhibited a subnanomolar level of cytotoxicity with an IC₅₀ of 0.17-0.94 nM. <b>37b3</b> induced DNA damage and led to tumor cell cycle arrest and apoptosis. We employed <b>37b3</b> as a payload to conjugate with trastuzumab to obtain the antibody-drug conjugate (ADC) T-PBA. T-PBA maintained its mode of target and internalization ability of trastuzumab. We demonstrated that T-PBA could be degraded through the lysosomal pathway to release the payload <b>37b3</b> after internalization. T-PBA showed a powerful killing effect on Her2-positive cancer cells <i>in vitro</i>. Furthermore, T-PBA significantly inhibited tumor growth in gastric and ovarian cancer xenograft mouse models without overt toxicity. Collectively, these studies suggest that T-PBA represents a promising new ADC that deserves further investigation.