Enhanced Intracellular Accumulation and Cytotoxicity of Ferrocene‐Ruthenium Arene Conjugates

• Published in: ChemPlusChem (Weinheim, Germany) Germany), 2020-05, Vol.85 (5), p.1034-1043
• Main Authors: Gelle, Donát, Lamač, Martin, Mach, Karel, Šimková, Ludmila, Gyepes, Róbert, Sommerová, Lucia, Martišová, Andrea, Bartošík, Martin, Vaculovič, Tomáš, Kanický, Viktor, Hrstka, Roman, Pinkas, Jiří
• Format: Article
• Language: English
• Subjects: antitumor agents; electrochemistry; ferrocene; metallocene; ruthenium
• ISSN: 2192-6506; 2192-6506
• DOI: 10.1002/cplu.202000022

Coordination of arenophilic Cp*Ru+ (Cp*=η5‐C5Me5) fragment to pendant aromatic ring(s) of either benzylferrocene (1) or dibenzylferrocene (2) gave air‐ and water‐stable dinuclear (4) or trinuclear (6) ferrocene‐ruthenium conjugates. The complexes were characterized by NMR, ESI‐MS, cyclic voltammetry (CV), elemental analysis, and the molecular structure of 4 was established by single crystal X‐ray diffraction. Contrary to the starting ferrocenes 1 and 2, conjugates 4 and 6 showed significant in vitro anticancer activity (up to IC50 0.6±0.2 μM) against various cancer cell lines (A2780, SK‐OV‐3, MDA‐MB‐231). Differential pulse voltammetry (DPV) showed that the intracellular accumulation of 4 was approximately twice that of 6 in all studied cell lines, which corresponds to a higher cytotoxicity of 4. Together we are stronger: Dinuclear and trinuclear ferrocene/cationic ruthenium arene conjugates show higher potency against selected cancer cell lines (A2780, SK‐OV‐3, MDA‐MB‐231) than the individual components. The ferrocene core involved in both conjugates allowed simple determination of their cellular uptake by differential pulse voltammetry (DPV). The dinuclear conjugate displays approximately twice the intracellular accumulation in comparison to the trinuclear one, which roughly corresponds to its higher cytotoxicity.