Synthesis and biological evaluation of thiosemicarbazone-based antibody–drug conjugates

Abstract

Metal chelators belonging to the di-pyridyl-thiosemicarbazone (DpTs) class have shown great promise as adjuvant therapeutics for treating cancer, with DpC and Dp44mT emerging as the lead candidates. Despite their efficacy, these molecules also induce various undesirable side effects due to insufficient cancer cell targeting, highlighting the need to improve their selectivity. Here, we present a first generation of DpT–antibody conjugates. To this end, we developed a facile synthesis to functionalize DpTs strategically with click-able azido linkers. Moreover, selective side-chain modification of the clinical antibody trastuzumab (Tras) with a complementary bis-alkyne moiety is described. Using this new chemistry, we conjugated four different azido DpTs to trastuzumab via a combination of oxidation-controlled quinone (SPOCQ) and strain-promoted alkyne–azide click (SPAAC) chemistry. We evaluated the antiproliferative activity of the resulting novel antibody–drug conjugates (ADCs) against MCF-7 and SK-BR-3 cell lines. Linker positioning on the DpT scaffold significantly influences the cytotoxicity of the conjugates. For instance, conjugating Tras at the ortho position on the Dp44mT scaffold is more efficacious than conjugating at the para position with IC50 values of 25.7 ± 5.5 nM and 103.5 ± 2.0 nM, respectively, against MCF-7 cells. Furthermore, we observe intriguing cell line-dependent activity of the ADCs with increased selectivity towards MCF-7 cells, providing novel insights into the cytotoxic activity of DpTs and their antibody conjugates.

Graphical abstract: Synthesis and biological evaluation of thiosemicarbazone-based antibody–drug conjugates

Supplementary files

Article information

Article type
Research Article
Submitted
18 Feb 2025
Accepted
27 May 2025
First published
26 Jun 2025
This article is Open Access
Creative Commons BY license

RSC Med. Chem., 2025, Advance Article

Synthesis and biological evaluation of thiosemicarbazone-based antibody–drug conjugates

N. Sheernaly, I. Shajan, A. Steinbrueck, B. Albada and N. Metzler-Nolte, RSC Med. Chem., 2025, Advance Article , DOI: 10.1039/D5MD00154D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements