Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo-immunotherapeutic combination regimens through the establishment of a long-term cancer immunity. None of the clinically used DNA-binding Pt II complexes is considered a Type II ICD inducer. We generated a series of Pt IIcarbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt-NHC and compared their efficiency in triggering ICD-related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent Pt II candidate with superior ICD properties. Crucially, the magnitude of ICD-associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER-localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. Scheme 1. Molecular structures of Type I and Type II ICD inducers including DOX, oxaliplatin, NKP1339, [Pt(ape)Cl 2 ] (ape = aminophosphonate ester), Pt-NHC, and PlatinER.

Indolo[3,2- d ][1]benzazepines (paullones), indolo[3,2- d ][2]benzazepines, and indolo[2,3- d ][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2- d ][2]benzazepine-derived ligands HL 1 – HL 4 and copper(II) complexes 1 – 4 . All compounds were characterized by spectroscopic methods ( 1 H and 13 C NMR, UV–vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2 and 3 , in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by 1 H NMR and UV–vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure–activity relationships were deduced from the comparison of anticancer activities of HL 1 – HL 4 and 1 – 4 with those of structurally similar paullone-derived ( HL 5 – HL 7 and 5 – 7 ) and latonduine-derived scaffolds ( HL 8 – HL 11 and 8 – 11 ). The high anticancer activity of the lead drug candidate 4 was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.

Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo-immunotherapeutic combination regimens through the establishment of a long-term cancer immunity. None of the clinically used DNA-binding Pt II complexes is considered a Type II ICD inducer. We generated a series of Pt IIcarbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt-NHC and compared their efficiency in triggering ICD-related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent Pt II candidate with superior ICD properties. Crucially, the magnitude of ICD-associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER-localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. Scheme 1. Molecular structures of Type I and Type II ICD inducers including DOX, oxaliplatin, NKP1339, [Pt(ape)Cl 2 ] (ape = aminophosphonate ester), Pt-NHC, and PlatinER.

Antitumor Agents M. J. R. Tham, M. V. Babak, and W. H. Ang report in their Research Article on page 19070 an anticancer platinum(II) complex that induces endoplasmic reticulum (ER) stress‐driven immunogenic cell death through localised generation of ROS in the ER.

Tumortherapeutika W. H. Ang et al. berichten in ihrem Forschungsartikel auf S. 19232 über einen Platin(II)‐Komplex, der durch die lokalisierte Generierung von reaktiven Sauerstoffspezies im endoplasmatischen Retikulum den immunogenen Zelltod induziert.