Hydrolysis chemistry of the metallocene dichlorides M(.eta.5-C5H5)2Cl2, M = titanium, vanadium, or zirconium. Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents

Toney, Jeffrey H.; Marks, Tobin J.

doi:10.1021/ja00290a033

Cited by 306 publications

(243 citation statements)

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“…The rate of Cp hydrolysis of both 1 and 13 in water at different pD values has been reported previously (see Table 3 [6,14]). Preliminary data for the hydrolysis of a number of carboxylate complexes, including 8 have been reported.…”

Section: Resultsmentioning

confidence: 69%

“…The rate of halide and Cp ring hydrolysis in titanocene dichloride 1 in water has been wellcharacterised [6]. Rapid …”

Section: Discussionmentioning

confidence: 99%

“…Cp2TiCI 2 1 undergoes rapid halide and cyclopentadienyl (Cp) hydrolysis to form cyclopentadiene (CpH) and dicyclopentadiene, particularly at pH >4.0 [6]. However, these hydrolysis products cause non-specific, local tumour inhibiting effects and do not exhibit the systemic antitumour activity of Cp2TiCI2 [1,7].…”

Section: Introductionmentioning

confidence: 99%

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Antitumour Metallocenes: Effect of DMSO on the Stability of Cp₂TiX₂and Implications for Anticancer Activity

Mokdsi

Harding

1998

Metal-Based Drugs

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Section: Resultsmentioning

confidence: 69%

“…The rate of halide and Cp ring hydrolysis in titanocene dichloride 1 in water has been wellcharacterised [6]. Rapid …”

Section: Discussionmentioning

confidence: 99%

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Antitumour Metallocenes: Effect of DMSO on the Stability of Cp₂TiX₂and Implications for Anticancer Activity

Mokdsi

Harding

1998

Metal-Based Drugs

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“…By conductivity, after a 50 min induction period associated with its dissolution, Toney 5 could estimate an effective net first order rate for cleavage of both chlorides in 1 of 0. ).…”

Section: Early Titanium Anti-cancer 'Mode(s) Of Action' Suggestionsmentioning

confidence: 99%

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

2017

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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'.

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“…Titanocene dichloride and budotitane possess the same limitation, low hydrolytic stability at physiological pH [15,17,26]. As a result, the mechanistic aspects and hydrolysis products of these antitumor species remain mostly uncharacterized.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, solution and solid state structure of titanium–maltol complex

Lamboy

Pasquale

Rheingold

et al. 2007

Inorganica Chimica Acta

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The reaction of Cp 2 TiCl 2 with two equivalents of maltol (3-hydroxy-2-methyl-4-pyrone) in water, at room temperature and pH of 5.4, leads to a complete replacement of Cp and chloride ligands affording, Ti(maltolato) 2 (OH) 2. The complex has been characterized by IR, NMR and ESI-MS spectroscopic and cyclic voltammetry methods. In DMSO-d 6 solution, the complex shows two isomers in a ratio of 4:1, in which one OH signal can be identified per isomer. This suggests that in solution the complex is monomeric, most likely a chiral cis-Ti(maltolato) 2 (OH) 2 and trans-Ti (maltolato) 2 (OH) 2 . The monomeric nature of the complex (in water/methanol 1:1) was verified by ESI-MS spectroscopy, showing a parent peak at 329 m/z. Electrochemical behavior of Ti (maltolato) 2 (OH) 2 using cyclic voltammetry experiments showed the complex undergoes irreversible reduction in aprotic solvents. In D 2 O solution, at pH of 8.4, the 1 H NMR spectrum of the complex shows a mixture of monomer and tetramer Ti(IV)-maltol complexes in a ratio of 1:1. The crystallization of Ti (maltolato) .686(7) Å, β= 97.678(4)° and V = 6824(4) Å 3 for Z = 4. Solid state structure determination of the Ti-maltol complex showed to be tetrameric, containing two bridging oxides (in cis position) and two bidentate maltol ligands per titanium in a pseudo-octahedral coordination geometry.

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Hydrolysis chemistry of the metallocene dichlorides M(.eta.5-C5H5)2Cl2, M = titanium, vanadium, or zirconium. Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents

Cited by 306 publications

References 0 publications

Antitumour Metallocenes: Effect of DMSO on the Stability of Cp₂TiX₂and Implications for Anticancer Activity

Antitumour Metallocenes: Effect of DMSO on the Stability of Cp₂TiX₂and Implications for Anticancer Activity

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

Synthesis, solution and solid state structure of titanium–maltol complex

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Hydrolysis chemistry of the metallocene dichlorides M(.eta.5-C5H5)2Cl2, M = titanium, vanadium, or zirconium. Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents

Cited by 306 publications

References 0 publications

Antitumour Metallocenes: Effect of DMSO on the Stability of Cp2TiX2and Implications for Anticancer Activity

Antitumour Metallocenes: Effect of DMSO on the Stability of Cp2TiX2and Implications for Anticancer Activity

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

Synthesis, solution and solid state structure of titanium–maltol complex

Contact Info

Product

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About

Antitumour Metallocenes: Effect of DMSO on the Stability of Cp₂TiX₂and Implications for Anticancer Activity

Antitumour Metallocenes: Effect of DMSO on the Stability of Cp₂TiX₂and Implications for Anticancer Activity