Cytotoxic Salan-Titanium(IV) Complexes: High Activity Toward a Range of Sensitive and Drug-Resistant Cell Lines, and Mechanistic Insights

The cytotoxicities of highly efficient salan-Ti ^IV complexes toward a range of cell lines, including drug-resistant cells, are reported along with preliminary mechanistic insights. Five salan-Ti ^IV complexes were investigated toward eight different human and murine cancer-derived cell lines, including colon, ovarian, lung, cervical, pancreatic, leukemic, skin, and breast. The salan complexes are more active toward the cells analyzed than cisplatin and the known titanium compound (bzac) ₂Ti(OiPr) ₂, and no cell line resistant to the salan complexes was identified. Moreover, the salan-Ti ^IV complexes are highly active toward both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780CisR) human ovarian cancer cell lines. Similarly, the salan complexes are cytotoxic toward multi-drug-resistant (ABCB1-expressing) mouse lymphoma cell lines HU-1 and HU-2. Importantly, minimal or no activity was observed toward primary murine cells (bone marrow, heart, liver, kidney, spleen, and lung), supporting selectivity for cancer cells. Additionally, the salan complexes maintain high cytotoxicity for up to 24h following exposure to cell culture medium, whereas reference complexes (bzac) ₂Ti(OiPr) ₂ and Cp ₂TiCl ₂ rapidly lose much of their activity upon exposure to medium, within ~1h. The upregulation of p53 followed by cell-cycle arrest in G ₁ phase is likely one mechanism of action of the salan complexes. Taken together, the results indicate that these compounds are selectively toxic to cancer cells and are able to circumvent two independent mechanisms of drug resistance, thus expanding the scope of their potential medicinal utility.