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

Musa, Mustapha; Abid, Mohammed; Bradshaw, Tracey D.; Boocock, David J.; Coveney, Clare; Argent, Stephen P.; Woodward, Simon

Abstract

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.

• Journal Article Type: Article
• Acceptance Date: Jan 18, 2024
• Online Publication Date: Feb 8, 2024
• Publication Date: Feb 22, 2024
• Deposit Date: Jan 22, 2024
• Publicly Available Date: Feb 12, 2024
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 4
• Pages: 2732-2744
• DOI: https://doi.org/10.1021/acs.jmedchem.3c01874
• Keywords: titanium complexes, phenolate ligands, anti-cancer, mode of action, proteomics
• Public URL: https://nottingham-repository.worktribe.com/output/30109252
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01874