Tripodal O-N-O Bis-Phenolato Amine Titanium(IV) Complexes Show High in vitro Anti-Cancer Activity: Tripodal O-N-O Bis-Phenolato Amine Titanium(IV) Complexes Show High in vitro Anti-Cancer Activity

The octahedral titanium(IV) complexes trans,mer-[Ti{(RN)-N-3(CH2C6H2-2-O-4-R-2-6-R-1)(2)}(2)] (R-1 = Me, OMe, Cl; R-2 = Me, OMe, F, Cl; R-3 = Me, Et; not all combinations) are synthesised in two steps from simple phenols in 36-53 % overall yield. The highly crystalline (4 X-ray structures) complexes are active against MCF-7 (breast) and HCT-116 (colon) cancer cell lines showing widely varying GI(50) values in the range 1-100 mu M depending on R-1-R-3. Highest activities are realised when R-1 = OMe and R-2, R-3 = Me (GI(50) ca. 1 mu M for MCF-7 and 2-3 mu M for HCT-116). These are respectively 8x and 3x times greater than the activities of cisplatin in the same cell lines. These titanium complexes show some significant selectivity for cancer cell lines; up to 7x higher in MCF-7 compared to non-cancer (MRC-5) fibroblast cells. Details of cellular mode of action indicators (cell cycle perturbation, Annexin V, gamma-H2AX, and caspase studies) that point to an apoptosis mode for the most active compound (R-1 = OMe and R-2, R-3 = Me) are also reported.||||||