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Synthesis of Pure Enantiomers of Titanium(IV) Complexes with Chiral Diaminobis(phenolato) Ligands and Their Biological Reactivity.

ABSTRACT: Racemic and enantiomerically pure titanium(IV) complexes with ortho-brominated or para-nitrated chiral diaminobis(phenolato) ligands were prepared with NH and NMe cyclohexyldiamino bridges through ligand to metal chiral induction. The hydrolytic behavior of the complexes was evaluated, identifying the N-methylated complex as the most stable. A representative NH complex hydrolyzed to first give a dimeric structure in solution as deduced by NMR diffusion measurements, followed by formation of clusters with higher nuclearity, as was supported by X-ray characterization of a tetranuclear cluster obtained in trace amounts following 30 days in water solutions. The cytotoxicity of the enantiomerically pure and racemic complexes was measured on HT-29 human colon cancer cell line based on the MTT assay; all stereochemical configurations of the N-methylated complex were inactive, whereas for the NH complexes, the racemic mixtures were mostly inactive but the pure enantiomers exhibited similarly high cytotoxicity, supporting a polynuclear active species. Analysis of the two enantiomers of the most active brominated complex for their cytotoxicity on human ovarian A2780, cisplatin resistant A2780cp and multi-drug-resistant A2780adr cell lines as well as for their apoptosis induction on the A2780 line revealed similar reactivity, supporting a similar mechanism for the two enantiomers.

SUBMITTER: Miller M

PROVIDER: S-EPMC6018713 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Synthesis of Pure Enantiomers of Titanium(IV) Complexes with Chiral Diaminobis(phenolato) Ligands and Their Biological Reactivity.

Miller Maya M Tshuva Edit Y EY

Scientific reports 20180626 1

Racemic and enantiomerically pure titanium(IV) complexes with ortho-brominated or para-nitrated chiral diaminobis(phenolato) ligands were prepared with NH and NMe cyclohexyldiamino bridges through ligand to metal chiral induction. The hydrolytic behavior of the complexes was evaluated, identifying the N-methylated complex as the most stable. A representative NH complex hydrolyzed to first give a dimeric structure in solution as deduced by NMR diffusion measurements, followed by formation of clus ...[more]

PMID: 29946136

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Project description:Oxoiron(IV) species have been found to act as the oxidants in the catalytic cycles of several mononuclear nonheme iron enzymes that activate dioxygen. To gain insight into the factors that govern the oxidative reactivity of such complexes, a series of five synthetic S = 1 [Fe(IV)(O)(L(N5))](2+) complexes has been characterized with respect to their spectroscopic and electrochemical properties as well as their relative abilities to carry out oxo transfer and hydrogen atom abstraction. The Fe=O units in these five complexes are supported by neutral pentadentate ligands having a combination of pyridine and tertiary amine donors but with different ligand frameworks. Characterization of the five complexes by X-ray absorption spectroscopy reveals Fe=O bonds of ca. 1.65 Å in length that give rise to the intense 1s?3d pre-edge features indicative of iron centers with substantial deviation from centrosymmetry. Resonance Raman studies show that the five complexes exhibit ?(Fe=O) modes at 825-841 cm(-1). Spectropotentiometric experiments in acetonitrile with 0.1 M water reveal that the supporting pentadentate ligands modulate the E(1/2)(IV/III) redox potentials with values ranging from 0.83 to 1.23 V vs. Fc, providing the first electrochemical determination of the E(1/2)(IV/III) redox potentials for a series of oxoiron(IV) complexes. The 0.4-V difference in potential may arise from differences in the relative number of pyridine and tertiary amine donors on the L(N5) ligand and in the orientations of the pyridine donors relative to the Fe=O bond that are enforced by the ligand architecture. The rates of oxo-atom transfer (OAT) to thioanisole correlate linearly with the increase in the redox potentials, reflecting the relative electrophilicities of the oxoiron(IV) units. However this linear relationship does not extend to the rates of hydrogen-atom transfer (HAT) from 1,3-cyclohexadiene (CHD), 9,10-dihydroanthracene (DHA), and benzyl alcohol, suggesting that the HAT reactions are not governed by thermodynamics alone. This study represents the first investigation to compare the electrochemical and oxidative properties of a series of S = 1 Fe(IV)=O complexes with different ligand frameworks and sheds some light on the complexities of the reactivity of the oxoiron(IV) unit.

Project description:High valent iron species are very reactive molecules involved in oxidation reactions of relevance to biology and chemical synthesis. Herein we describe iron(iv)-tosylimido complexes [FeIV(NTs)(MePy2tacn)](OTf)2 (1(IV)[double bond, length as m-dash]NTs) and [FeIV(NTs)(Me2(CHPy2)tacn)](OTf)2 (2(IV)[double bond, length as m-dash]NTs), (MePy2tacn = N-methyl-N,N-bis(2-picolyl)-1,4,7-triazacyclononane, and Me2(CHPy2)tacn = 1-(di(2-pyridyl)methyl)-4,7-dimethyl-1,4,7-triazacyclononane, Ts = Tosyl). 1(IV)[double bond, length as m-dash]NTs and 2(IV)[double bond, length as m-dash]NTs are rare examples of octahedral iron(iv)-imido complexes and are isoelectronic analogues of the recently described iron(iv)-oxo complexes [FeIV(O)(L)]2+ (L = MePy2tacn and Me2(CHPy2)tacn, respectively). 1(IV)[double bond, length as m-dash]NTs and 2(IV)[double bond, length as m-dash]NTs are metastable and have been spectroscopically characterized by HR-MS, UV-vis, 1H-NMR, resonance Raman, Mössbauer, and X-ray absorption (XAS) spectroscopy as well as by DFT computational methods. Ferric complexes [FeIII(HNTs)(L)]2+, 1(III)-NHTs (L = MePy2tacn) and 2(III)-NHTs (L = Me2(CHPy2)tacn) have been isolated after the decay of 1(IV)[double bond, length as m-dash]NTs and 2(IV)[double bond, length as m-dash]NTs in solution, spectroscopically characterized, and the molecular structure of [FeIII(HNTs)(MePy2tacn)](SbF6)2 determined by single crystal X-ray diffraction. Reaction of 1(IV)[double bond, length as m-dash]NTs and 2(IV)[double bond, length as m-dash]NTs with different p-substituted thioanisoles results in the transfer of the tosylimido moiety to the sulphur atom producing sulfilimine products. In these reactions, 1(IV)[double bond, length as m-dash]NTs and 2(IV)[double bond, length as m-dash]NTs behave as single electron oxidants and Hammett analyses of reaction rates evidence that tosylimido transfer is more sensitive than oxo transfer to charge effects. In addition, reaction of 1(IV)[double bond, length as m-dash]NTs and 2(IV)[double bond, length as m-dash]NTs with hydrocarbons containing weak C-H bonds results in the formation of 1(III)-NHTs and 2(III)-NHTs respectively, along with the oxidized substrate. Kinetic analyses indicate that reactions proceed via a mechanistically unusual HAT reaction, where an association complex precedes hydrogen abstraction.

Dataset Information

Synthesis of Pure Enantiomers of Titanium(IV) Complexes with Chiral Diaminobis(phenolato) Ligands and Their Biological Reactivity.

Publications

Synthesis of Pure Enantiomers of Titanium(IV) Complexes with Chiral Diaminobis(phenolato) Ligands and Their Biological Reactivity.

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