Using titanium complexes to defeat cancer: the view from the shoulders of titans

Abstract

When the first titanium complex with anticancer activity was identified in the 1970s, it was attractive, based on the presence of the dichloride unit in TiCl 2 Cp 2 (Cp = η-C 5 H 5 ) 2 , to assume its mode of biological action was closely aligned with cisplatin [cis-PtCl 2 (NH 3 ) 2 ]. Over the intervening 40 years however a far more complicated picture has arisen indicating multiple cellular mechanisms of cellular action can be triggered by titanium anti-cancer agents. This tutorial review aims to unpick the historical data and provide new researchers, without an explicit cancer biology background, a contemporary interpretation of both older and newer literature and to review the best techniques for attaining the identities of the biologically active titanium species and how these interact with the cancer cellular machinery. Key learning points(1) Understanding the problems in defining 'modes of action' in order to effectively design small molecular titanium-based therapeutic, agents when moving beyond simple 'structure vs. activity' correlations. (2) The dangers of over generalisation in historical 'mode of action' proposals in the absence of rigorous control experiments leading to proposals not fully in line with all (especially later) observations. (3) Titanium induced cellular morphology changes and contemporary thoughts on mode(s) of actionpresented in a way chemical scientists can 'get to grips with them' -understanding the hall marks of cellular death modes induced by titanium anti-cancer agents. (4) Modern tools for probing Ti-drug mechanisms of action, including: chiral probe complexes, added external proteins (transferrin, serum albumin); titanium solution speciation, and an overview of contemporary chemical-biology techniques of relevance to discovery of 'modes/mechanisms of action'.

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

“…However, development of resistance to these drugs and the toxicity of the Pt ion led to a search for other metal‐based drugs. Among the transition metals tested, two titanium‐based complexes—budotitane and titanocene dichloride—reached clinical trials, but failed due to rapid hydrolysis and the formation of undefined aggregates . To overcome these obstacles, our laboratory developed a new family of titanium(IV) complexes based on phenolato ligands .…”

“…Amongt he transition metalstested, two titanium-based complexes-budotitane and titanocene dichloride-reached clinical trials, but failed due to rapid hydrolysis and the formation of undefineda ggregates. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] To overcome these obstacles, our laboratory developed an ew family of titanium(IV) complexes based on phenolato ligands. [30][31][32][33][34][35][36][37][38][39][40][41][42] In particular,d iaminobis(phenolato)-bis(alkoxo)Ti IV (phenolaTi,F igure 1) demonstrated remarkable stability in aqueous media and an extended shelf life, along with enhanced in vitro cytotoxicity toward various cancer cell types.…”

Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)

“…Like Ru360′, several Ti IV complexes show a decreased cellular uptake in the presence of FBS. In this case, this result has been attributed to tight binding of the complexes to biomolecules, such as albumin, which limits their release in cells …”

Electrochemical Study of Highly Substituted Titanocene Dihalides

“…Titanocene dichloride 1 a ([Cp 2 TiCl 2 ], Cp = η 5 -C 5 H 5 ) was the first non-platinum organometallic drug that entered clinical trials. Although the clinical trials were discontinued due to severe side effects, poor solubility, and low efficacy in vivo [4][5], in the last decade renewed research interest in new anti-cancer titanocene derivatives [6][7][8][9] is evident. The present study is therefore focused on titanocene difluorides and their comparison with analogous dichlorides.…”