Ruthenacarborane and Quinoline: A Promising Combination for the Treatment of Brain Tumors

Abstract

Gliomas and glioblastomas are very aggressive forms of brain tumors, prone to the development of a multitude of resistance mechanisms to therapeutic treatments, including cytoprotective autophagy. In this work, we investigated the role and mechanism of action of the combination of a ruthenacarborane derivative with 8-hydroxyquinoline (8-HQ), linked via an ester bond (complex 2), in rat astrocytoma C6 and human glioma U251 cells, in comparison with the two compounds alone, i.e., the free carboxylic acid (complex 1) and 8-HQ, and their non-covalent combination ([1 + 8-HQ], in 1:1 molar ratio). We found that only complex 2 was able to significantly affect cellular viability in glioma U251 cells (IC50 11.4 μM) via inhibition of the autophagic machinery, most likely acting at the early stages of the autophagic cascade. Contrary to 8-HQ alone, complex 2 was also able to impair cellular viability under conditions of glucose deprivation. We thus suggest different mechanisms of action of ruthenacarborane complex 2 than purely organic quinoline-based drugs, making complex 2 a very attractive candidate for evading the known resistances of brain tumors to chloroquine-based therapies.

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…Ruthenium and osmium are a class of transition metals widely used in cancer therapy. 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 Complexes containing electron-deficient ruthenium and osmium carborane were reported by the Sadler and Hanna groups. 50 , 51 The redox-active response of these carborane-containing complexes to biomolecules have resulted in their potential application in cancer therapy.…”

The Role of Ruthenium Compounds in Neurologic Diseases: A Minireview

“…linked by ester bond, to these same compounds alone (free carboxylic acid and 8-HQ) in mouse astrocytoma C6 cells and U251 human glioma, showed promising results by inhibiting the autophagy mechanism of U251 glioma cells, as well as making them unfeasible even under conditions of glucose deprivation (where 8-HQ loses activity) (Drača et al, 2021).…”

(7,8-Dicarba-nido-undecaboran-7-yl)acetic acid: synthesis of individual enantiomers and the first example of the determination of the absolute configuration of chiral monosubstituted nido-carborane

“…Derivatives of planar-chiral ( nido -carboran-7-yl)-substituted carboxylic acids are of interest as antitumor agents with an original mechanism of action, 13 and as bases for iodine- 14 and astatine-containing radiopharmaceuticals. 15 To the best of our knowledge, there are no literature examples of preparation of enantiomerically pure compounds of this group.…”