Probing the Mechanism of Action of Bis(phenolato) Amine (ONO Donor Set) Titanium(IV) Anticancer Agents

The need for anticancer therapies that overcome metallodrug
resistance
while minimizing adverse toxicities is targeted, herein, using titanium
coordination complexes. Octahedral titanium­(IV) trans,mer-[Ti­{R1N­(CH2–2-MeO-4-R1-C6H2)2}2] [R1 = Et, allyl, n-Pr, CHO, F, CH2(morpholino), the latter from the formyl derivative; R2 = Me, Et; not all combinations] are attained from Mannich reactions
of commercial 2-methoxyphenols (27–74% overall yield, 2 steps).
These crystalline (four X-ray structures) Ti­(IV)-complexes are active
against MCF-7, HCT-116, HT-29, PANC-1, and MDA-MB-468 cancer cell
lines (GI50 = 0.5–38 μM). Their activity and
cancer selectivity (vs nontumor MRC-5 cells) typically exceeds that
of cisplatin (up to 16-fold). Proteomic analysis (in MCF-7) supported
by other studies (G2/M cell cycle arrest, ROS generation, γH2AX
production, caspase activation, annexin positivity, western blot,
and kinase screens in MCF-7 and HCT-116) suggest apoptosis elicited
by more than one mechanism of action. Comparison of these data to
the modes of action proposed for salan Ti­(IV) complexes is made.