Biological evaluation of novel thiomaltol-based organometallic complexes as topoisomerase IIα inhibitors.

Topoisomerase IIα (topo2α) is an essential nuclear enzyme involved in DNA replication, transcription, recombination, chromosome condensation, and highly expressed in many tumors. Thus, topo2α-targeting has become a very efficient and well-established anticancer strategy. Herein, we investigate the cytotoxic and DNA-damaging activity of thiomaltol-containing ruthenium-, osmium-, rhodium- and iridium-based organometallic complexes in human mammary carcinoma cell lines by means of several biological assays, including knockdown of topo2α expression levels by RNA interference. Results suggest that inhibition of topo2α is a key process in the cytotoxic mechanism for some of the compounds, whereas direct induction of DNA double-strand breaks or other DNA damage is mostly rather minor. In addition, molecular modeling studies performed for two of the compounds (with Ru(II) as the metal center) evinces that these complexes are able to access the DNA-binding pocket of the enzyme, where the hydrophilic environment favors the interaction with highly polar complexes. These findings substantiate the potential of these compounds for application as antitumor metallopharmaceuticals.