Cobalt bis(dicarbollide) (COSAN) is a metallacarborane used as a versatile pharmacophore to prepare biologically active hybrid organic-inorganic compounds or to improve the pharmacological properties of nucleosides, antisense oligonucleotides, and DNA intercalators. Despite these applications, COSAN interactions with nucleic acids remain unclear, limiting further advances in metallacarborane-based drug development. Although some studies showed that COSAN intercalates into DNA, COSAN-containing intercalators do not, and while COSAN shows low cytotoxicity, intercalators are often highly toxic. The present study aimed at comprehensively characterizing interactions between COSAN and DNA using a wide range of techniques, including UV-Vis absorption, circular (CD) and linear (LD) dichroism, nuclear magnetic resonance (NMR) spectroscopy, thermal denaturation, viscosity, differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), and equilibrium dialysis measurements. Our results showed that COSAN has no effect on DNA structure, length, stability, or hybridization, with no or only faint signs of COSAN binding to DNA. Moreover, DNA is not necessary for COSAN to induce cytotoxicity at high concentrations, as shown by in vitro experiments. These findings demonstrate that COSAN is a DNA-neutral pharmacophore, thus confirming the general safety and biocompatibility of metallacarboranes and opening up new opportunities for further developing metallacarborane-based drugs.

Department of Physical and Macromolecular Chemistry Faculty of Science Charles University Hlavova 2030 128 40 Prague 2 Czechia

Laboratory of Biomedical Chemistry Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences 12 Rudolf Weigl St 53 114 Wrocław Poland

Laboratory of Experimental Anticancer Therapy Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences 12 Rudolf Weigl St 53 114 Wrocław Poland

NMR Laboratory Faculty of Science Charles University Hlavova 2030 128 40 Prague 2 Czechia

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Chemistry of Carbon-Substituted Derivatives of Cobalt Bis(dicarbollide)(1-) Ion and Recent Progress in Boron Substitution