Hinged Bipodal Furoylthiourea-Based Ru(II)-Arene Complexes: Effect of (ortho, meta, or para)-Substitution on Coordination and Anticancer Activity

We set out to design and synthesize bipodal ligands with the phenyl group as the spacer and varied the substitution on the spacer between ortho (L1), meta (L2), and para (L3). The respective ligands and complexes containing either p-cymene (PL1-PL3) or benzene (BL1-BL3) as the arene unit were synthesized and characterized successfully. The influence of the ligands due to substitution change on their coordination behavior was quite minimal; however, the differences were seen in the anticancer activity of the complexes. DFT studies revealed the structural variations between the three different substitutions, which was further confirmed by single-crystal X-ray diffraction studies. The anticancer activity of the complexes could be correlated with their rate of hydrolysis and their lipophilicity index as determined by UV-visible spectroscopy. The cell death mechanism of the active complexes was deduced to be apoptotic via staining assays, flow cytometry, and Western blot analysis.

Automated summary

We designed and synthesized bipodal ligands with varying substitution on the phenyl group spacer. Ligands and complexes with different arene units were successfully synthesized and characterized. The coordination behavior of the ligands was minimally influenced by substitution change, but differences were observed in the anticancer activity of the complexes. DFT and X-ray diffraction studies revealed structural variations between the different substitutions, and UV-visible spectroscopy determined the correlation between anticancer activity, hydrolysis rate, and lipophilicity index of the complexes. Staining assays, flow cytometry, and Western blot analysis confirmed the apoptotic cell death mechanism of the active complexes.