Laboratory of Biomedical Chemistry, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl St., 53-114 Wrocław, Poland.
Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 2030, 128 40 Prague 2, Czechia.
Dalton Trans. 2023 Aug 1;52(30):10338-10347. doi: 10.1039/d3dt01836a.
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 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.
钴双(二碳硼烷)(COSAN)是一种金属碳硼烷，可用作多功能药效团，制备具有生物活性的杂化有机-无机化合物，或改善核苷、反义寡核苷酸和 DNA 嵌入剂的药理学性质。尽管有这些应用，COSAN 与核酸的相互作用仍不清楚，限制了基于金属碳硼烷的药物开发的进一步进展。尽管一些研究表明 COSAN 嵌入 DNA 中，但含 COSAN 的嵌入剂则不然，虽然 COSAN 表现出低细胞毒性，但嵌入剂通常毒性很高。本研究旨在使用多种技术全面表征 COSAN 与 DNA 之间的相互作用，包括紫外-可见吸收、圆二色性(CD)和线二色性(LD)、核磁共振(NMR)光谱、热变性、粘度、差示扫描量热法(DSC)、等温滴定量热法(ITC)和平衡透析测量。我们的结果表明，COSAN 对 DNA 结构、长度、稳定性或杂交没有影响，COSAN 与 DNA 的结合没有或只有微弱的迹象。此外，高浓度的 COSAN 诱导细胞毒性不需要 DNA，实验表明。这些发现表明 COSAN 是一种 DNA 中性药效团，从而证实了金属碳硼烷的一般安全性和生物相容性，并为进一步开发基于金属碳硼烷的药物开辟了新的机会。
