Highly Selective Apoptotic Cell Death Induced by Halo‐Salane Titanium Complexes

Immel, Timo A.; Dębiak, Małgorzata; Groth, Ulrich; Bürkle, Alexander; Huhn, Thomas

doi:10.1002/cmdc.200900038

Cited by 34 publications

(37 citation statements)

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“…[43][44][45] In the case of aryl unsubstituted ligand (Ph H N Me ) 2 , salicylaldehyde was reacted with ethylenediamine, then the resulting imine was reduced with sodium borohydride and subsequently methylated by reductive amination to give the desired salan. [46] Finally, metalation of these salans with different titanium alkoxides TiA…”

Section: Resultsmentioning

confidence: 99%

“…[43,47] To remove trace impurities, all compounds were recrystallized at least once prior to cytotoxicity studies. Purities were proven by combustion analysis.…”

Section: Resultsmentioning

confidence: 99%

“…[48] The cytotoxicity was studied in two different cell lines: the human cervix carcinoma cell line HeLa S3 and the Hep G2 cell line, an established human hepatocarcinoma cell line with epithelial morphology. [43] Cisplatin was used as a reference substance in all Scheme 1. Synthesis of salan ligands by Mannich condensation.…”

Section: Resultsmentioning

confidence: 99%

“…Their IC 50 values are comparable to cisplatin and, in contrast to their alkyl-substituted congeners, they almost exclusively induce apoptotic cell death. [43] Herein we describe the synthesis, biological evaluation, and hydrolytic behavior of a library of more than 40 alkyland halogen-substituted titanium salan complexes. The obtained data are discussed with respect to structure-activity relations and the influence of hydrolysis on cytotoxicity.…”

Section: A C H T U N G T R E N N U N G (O Iprmentioning

confidence: 99%

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Cytotoxic Titanium Salan Complexes: Surprising Interaction of Salan and Alkoxy Ligands

Immel

Groth

Huhn

2010

Chemistry A European J

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The synthesis, biochemical evaluation, and hydrolysis studies of a wide selection of alkyl- and halogen-substituted titanium salan alkoxides are presented herein. A systematic change in the employed alkoxides revealed that both the bulk of the salan ligands and the steric demand of the labile ligands are of great importance for the obtained biological activity. Surprisingly, these two factors are not independent from each other; lowering the steric demand of the alkoxide of a hitherto nontoxic complex renders it cytotoxic. Therefore, our data suggest that the overall size of the complex exerts a strong influence on its biological activity. To decide whether the correlation between the cytotoxicity and the steric demand of the whole complex is merely based on an altered hydrolysis or on the interaction with biomolecules, the behavior of selected complexes under hydrolytic conditions and the influence of transferrin were investigated. Complexes differing only in their labile alkoxy ligands gave the same hydrolysis products with similar hydrolysis rates but displayed cytotoxicities that differed in the range of one order of magnitude. Thus, it seems that the hydrolysis product is not the active species but rather that the unhydrolysed complex is important for the first interaction with a biomolecule. This promoted the idea of hydrolysis being a detoxification pathway. In accordance with the above conclusion, chloro-substituted complex [Ti(Ph(Cl)N(Me))(2)(O(iPr))(2)] displayed a high cytotoxicity (IC(50) approximately 5 microM) and surprisingly high hydrolytic stability (t(1/2)=108 h). These findings, together with the observed cytotoxicity in a cisplatin-resistant cell line, make halo-substituted salan complexes an interesting target for further studies.

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Section: Resultsmentioning

confidence: 99%

“…[43,47] To remove trace impurities, all compounds were recrystallized at least once prior to cytotoxicity studies. Purities were proven by combustion analysis.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: A C H T U N G T R E N N U N G (O Iprmentioning

confidence: 99%

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Cytotoxic Titanium Salan Complexes: Surprising Interaction of Salan and Alkoxy Ligands

Immel

Groth

Huhn

2010

Chemistry A European J

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“…In 2009 Huhn reported that 10-11 were able to induce high cytotoxicity toward cervix tumour HeLa S3 cells (Figure 10). 30 Highly selective apoptotic (˃95%) induction was attained for 10, whereas necrosis accounted for ~5 0% cell death with 11. Salan-based-Ti IV complexes of formula 12 were also reported to be highly active against various tumour cell lines but also against cisplatin-resistant human ovarian cancer cell lines (A2780CisR) and multi-drug resistant (ABCB1-expressing) mouse lymphoma cell lines HU-1 and HU-2.…”

Section: Recent Findings In Titanium Anti-cancer 'Mode(s) Of Action'mentioning

confidence: 97%

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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Coordination Chemistry and Applications of Salen, Salan and Salalen Metal Complexes

Bellemin‐Laponnaz

Dagorne

2012

Patai's Chemistry of Functional Groups

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The present contribution summarizes and highlights the essential coordination features and applications of salen‐supported metal complexes. The use of salen complexes in homogeneous (and asymmetric) catalysis constitutes a major part of this chapter as salen‐type (and closely related) ligands have undoubtedly established themselves as “privileged” supporting ligands in catalysis over the past 20 years. The interest of such tetradentate chelating ligands in various other applications, including the suitability of salen metal complexes for medical applications and as building blocks for the synthesis of well‐defined polymetallic assemblies, will also be briefly discussed.

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Highly Selective Apoptotic Cell Death Induced by Halo‐Salane Titanium Complexes

Cited by 34 publications

References 47 publications

Cytotoxic Titanium Salan Complexes: Surprising Interaction of Salan and Alkoxy Ligands

Cytotoxic Titanium Salan Complexes: Surprising Interaction of Salan and Alkoxy Ligands

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

Coordination Chemistry and Applications of Salen, Salan and Salalen Metal Complexes

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