In-cell Catalysis by Tethered Organo-Osmium Complexes Generates Selectivity for Breast Cancer Cells.

Autor: Coverdale JPC; School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B15 2TT, UK.; Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK., Bedford RA; School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B15 2TT, UK., Carter OWL; Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK., Cao S; School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B15 2TT, UK., Wills M; Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK., Sadler PJ; Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2024 Aug 01; Vol. 25 (15), pp. e202400374. Date of Electronic Publication: 2024 Jul 09.
DOI: 10.1002/cbic.202400374
Abstrakt: Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.
(© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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