Platinum(II) complexes with tris(2-carboxyethyl)phosphine, X-ray structure and reactions with polar solvents and glutathione

doi:10.1016/j.jorganchem.2015.05.050

Journal of Organometallic Chemistry

Volume 791, 15 August 2015, Pages 124-129

https://doi.org/10.1016/j.jorganchem.2015.05.050 Get rights and content

Highlights

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Cis and trans Pt(II) complexes with P(C₂H₄COOH)₃ (TCEP), reductant of S–S bond.
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Trans-[PtCl₂(TCEP)₂] is square planar and cis-[PtCl₂(TCEP)₂] is distorted square planar.
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Trans-[PtCl₂(TCEP)₂] in H₂O isomerizes to cis complexes with TCEP-κO,κP ligands.
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PtCl₂(TCEP)₂ complexes react with glutathione forming Pt–S and Pt–NH cysteinyl bonds.
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PtCl₂(TCEP)₂ are good model complexes for investigation reactions with biomolecules.

Abstract

It has recently been found that P(C₂H₄COOH)₃ (TCEP), used in the reduction of S–S bonds, promoted reaction of cisplatin with Sp1 zinc finger protein and Cu(I) transporters. However Pt complexes with TCEP were not investigated. New platinum(II) complexes with (TCEP): trans-[PtCl₂(TCEP)₂] (1) and cis-[PtCl₂(TCEP)₂]·1.25H₂O (2) were fully characterized by IR, ¹H, ¹³C, ³¹P, ¹⁹⁵Pt NMR and ESI-MS spectroscopic techniques. Structures of trans-[PtCl₂{P(C₂H₄COOD)₃}₂] (1a) and cis-[PtCl₂(TCEP)₂]·1.25H₂O (2) have been determined by X-ray crystallography. Complexes are stable in non-aqueous DMSO and DMF. In aqueous solutions Cl ligands are substituted by COO groups of phosphines. In the mixtures DMSO + H₂O and DMF + H₂O coordination of COO groups proceeds to a lesser extent and 1 partly isomerizes forming cis-[PtCl₂(TCEP)₂] and cis-[PtCl{P(C₂H₄COOH)₃-κP}{P(C₂H₄COOH)₂(C₂H₄COO)-κO,κP}]. The latter complex is also formed in solution of 2 in DMSO + H₂O and DMF + H₂O. The degrees of isomerization and substitution of Cl ligands in aqueous solutions are higher. NMR data indicate that complexes interact with reduced glutathione (GSH). Compound 2 in D₂O forms complex with GS ligand coordinated to platinum via S atom and NH cysteinyl group.

Graphical abstract

Structures and reactivity of Pt(II) complexes with P(C₂H₄COOH)₃ (TCEP), reductant of S–S bonds and promoter of reaction of cisplatin with Zn finger protein and Cu(I) transporters, were investigated. TCEP in nonaqueous solvent is coordinated via P atom but in water through P and O atoms. Complexes coordinate glutathione (GSH) via S atom and NHcys group.

Introduction

Platinum complexes belong to the compounds most frequently used in anticancer chemotherapy [1], [2], [3], [4], [5], [6]. Very intense investigations of platinum-based antitumor chemotherapeutics has begun since discovery of antitumor activity of cis-[PtCl₂(NH₃)₂] by Rosenberg in 1969 [7]. Platinum compounds are very effective for the treatment of ovarian and testicular cancers and in combinations with other antitumor agents are used in the therapy of many carcinomas, e.g. bladder, small lung, head and neck tumors. Platinum anticancer agents most frequently contain nitrogen, oxygen and chloride ligands. The highest activity has been shown by cis complexes, however, it has been found that trans complexes are effective against different cancer cells than cis compounds [5], [6]. Antitumor activity of phosphine platinum complexes was investigated to a lesser extent [5], [6], [8], [9], [10], [11], [12] than that of compounds with nitrogen and oxygen ligands. The phosphine complexes exhibit cytotoxic activity against cisplatin resistant tumor cells and sometimes are more active than cisplatin.

Tris(2-carboxyethyl)phosphine P(CH₂CH₂COOH)₃ (TCEP) is a reducing agent frequently used in biochemistry to break disulfide bond in peptides, proteins and other compounds containing S–S bond [13], [14], [15], [16]. It is now often used instead of dithiothreitol (DTT), which readily reduce the nitroxide spin probes used in EPR spectroscopy and in the presence of ubiquitous Fe(III) and Ni(II) compounds is catalytically oxidized. Therefore DTT is not stable in the reduced form for a long times. These problems can be circumvented by using phosphines showing relatively strong reducing properties. Very convenient is application of TCEP, which in aqueous solutions is stable, odorless and stoichiometrically and irreversibly reduces disulfides:RSSR + P(CH₂CH₂COOH)₃ + H₂O → 2RSH + OP(CH₂CH₂COOH)₃

It can be applied over a wide pH range. TECP forms complexes with transition metals. Coordination compounds with Zn(II) [17], Ni(II), Cu(II), Zn(II), Cd(II), Pb(II) [18], Co(III) [19] and Fe(I) [20] were investigated and X-ray structures of Zn(II), Cd(II), Co(III) and Fe(I) complexes were determined. In all complexes TCEP is coordinated via P atom and COO groups except Fe(I) compound, in which it is bonded via P atom. In platinum(II) compound with 3-(di(2-methoxyphenyl)phosphanyl)propionate trans-[PtCl{P(C₆H₄OMe)₂(CH₂CH₂COOH)-κP}{P(C₆H₄OMe)₂(CH₂CH₂COO)-κCOO,κP}] one phosphine is a chelate ligand bound via P atom and COO group, while the other is terminal ligand coordinated via phosphorus [21]. These examples indicate that phosphine ligands containing PCH₂CH₂COOH moiety can be coordinated to metal atoms via P atom and COO group. Recently TCEP was used for reactivity studies between cisplatin, oxaliplatin and model proteins. Due to the presence of redox active cysteine residue, investigations of interaction of proteins with metal complexes are typically performed in the presence of TCEP as reducing agent. It was found that cisplatin interacts with Cu(I) transporters ATP7B, Atox1 [22], [23], [24] and Sp1 zinc finger protein [25]. Recently discovered that TCEP significantly promoted the reaction of cisplatin with Sp1 zinc finger protein [25]. Structure of Pt(Atox1) (TCEP) was determined [24]. The Pt(II) atom has square-planar coordination with two S atoms of Cys in trans coordinating sites. The remaining positions are occupied by amide N atom of Cys and TCEP coordinated via P atom [24]. However, platinum complexes with TCEP were not obtained and investigated. Here we report complexes cis-[PtCl₂(TCEP)₂] and trans-[PtCl₂(TCEP)₂], their reactions in solutions and interaction with reduced glutathione, an important cellular antioxidant reacting with platinum anticancer agents.

Section snippets

Materials and physical measurements

Reagents and solvents (analytical grade) were purchased from the Polish company POCH, Sigma–Aldrich and ABCR Gmbh and were used as received. Complexes cis-[PtCl₂(CH₃CN)₂] and trans-[PtCl₂(CH₃CN)₂] were prepared according to the reported method [26]. Infrared spectra (KBr pellets and nujol) were recorded with a Bruker IFS 113v and Bruker 66/s spectrometers, ¹H, ¹³C, ³¹P and ¹⁹⁵Pt NMR spectra on a Bruker AMX 300 and Bruker Avance 500 spectrometers. Proton chemical shifts (δ) were reported with

Properties and structures of compounds in solid state

Reactions of K₂[PtCl₄] or [PtCl₂(CH₃CN)₂] with tris(2-carboxyethyl)phosphine P(CH₂CH₂COOH)₃ (TCEP) give trans-[PtCl₂{P(C₂H₄COOH)₃}₂] (1) and cis-[PtCl₂{P(C₂H₄COOH)₃)₂]·1.25H₂O (2). Complex (1) is formed in the reactions of platinum chloride complexes at Pt:P molar ratio equal to 1: 1 after several minutes at elevated temperatures. However, at molar ratio of Pt: P = 1: 2 pure cis compound is formed. Even trans-[PtCl₂(CH₃CN)₂] in reaction with TCEP (Pt: P = 1: 2) at room temperature after 24 h

Conclusions

Structures of new square-planar platinum(II) complexes with tris(2-carboxyethyl)phosphine P(CH₂CH₂COOH)₃: trans-[PtCl₂{P(C₂H₄COOH)₃}₂] (1) and cis-[PtCl₂{P(C₂H₄COOH)₃}₂]·1.25H₂O (2) have been determined. Their properties in solution were investigated with ¹H, ¹³C, ³¹P, ¹⁹⁵Pt NMR and ESI-MS spectroscopic techniques. In d₆-DMSO and d₇-DMF solutions square planar complexes are stable. However, in d₆-DMSO + D₂O and d₇-DMF + D₂O mixtures, trans compound partly undergoes isomerization to cis

References (36)

N. Cutillas et al.
Coord. Chem. Rev.
(2013)
U. Kalinowska-Lis et al.
Coord. Chem. Rev.
(2008)
A.G. Quiroga
J. Inorg. Biochem.
(2012)
A.G. Quiroga et al.
Polyhedron
(2011)
S.S. Rhee et al.
Anal. Biochem.
(2004)
P. Liu et al.
J. Am. Soc. Mass Spectrom.
(2010)
D.A. Knight et al.
Polyhedron
(2008)
B. Trettenbrein et al.
Inorg. Chim. Acta
(2011)
M.L. Mena et al.
Talanta
(2013)
K. Leonhardt et al.
J. Biol. Chem.
(2009)

A.G. Orpen et al.

J. Organometal. Chem.

(1998)

N.J. Wheate et al.

Dalton Trans.

(2010)

I. Kostova

Recent Pat. Anti-Cancer Drug Discov.

(2006)

V. Brabec et al.

Platinum-Based Drugs

B. Rosenberg et al.

Nature

(1969)

M. Frezza et al.

J. Med. Chem.

(2011)

W. Henderson et al.

J. Chem. Soc. Dalton Trans.

(2000)

H. Samoueia et al.

J. Organometal. Chem.

(2011)

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Reactivity of NiII, PdII and PtII complexes bearing phosphine ligands towards ZnII displacement and hydrolysis in Cis<inf>2</inf>His<inf>2</inf> and Cis<inf>3</inf>His zinc-fingers domains
2023, Journal of Inorganic Biochemistry
Citation Excerpt :
Phosphines (PR3) have been proved to modulate the reactivity of the metal complexes through the modification of the R groups attached to phosphorus as shown by mechanistic studies performed through 31P NMR. Also, these ligands can stabilize lower oxidation states through backbonding, depending on the nature of R, and decrease the speed of unfavorable substitution reactions [17,22,24–27]. The first mechanistic studies of medicinal gold complexes suggested phosphines were required for the biological activity, which was later shown to be wrong [16].
A systematic study of the effect of phosphine and bis-phosphine ligands in the interaction of Ni^II, Pd^II, and Pt^II complexes with two classes of zinc fingers was performed. The Cys₂His₂, finger 3 of specific protein-1, and the Cys₂HisCys C-terminal zinc finger of nucleocapsid protein 7 of the HIV-1 were used as models of the respective class. In general, phosphine ligands favor the metal binding to the peptide, although the bis-phosphine ligands produce more specific binding than the monodentate. In the case of nickel complexes, the interaction of Ni^II ions with the sequence SKH, present in Cys₂His₂, results in hydrolysis, contrasting to the preferred zinc ejection produced by the Ni^II complexes with chelating phosphines, producing Ni(bis-phosphine) fingers. In the absence of the SKH sequence, zinc ejection is observed with the formation of nickel fingers, with reactivity dependent on the phosphine. On the other hand, Pd(phosphines) produces Pd₂ fingers in the case of triphenylphosphine with the phosphine coordinated as intermediate species. The bis-phosphine ligands produce very clean spectra and a stable signal Pd(bis-phosphine)finger. Interestingly, phosphines produce very reactive platinum complexes, which eject zinc and promote peptide hydrolysis. The results reported here are relevant to the understanding of the mechanism of these interactions and how to modulate metallocompounds for zinc finger interference.
Multitopic metal–organic carboxylates available as supramolecular building units
2023, Coordination Chemistry Reviews
Citation Excerpt :
The bidentate-P,O and tridentate-P,O2 binding modes of H3L30 have been observed in palladium(II) and cobalt(III) complexes [100,101]. The octahedral M6E8L6 (M: transition metals, E: chalcogenides, L: protecting ligands) clusters exhibit one of the ubiquitous motifs of metal chalcogenide cluster compounds [102]. Various monodentate ligands, such as CO, CN–, halides, H2O, alkoxides, pyridines, thiols, and phosphines, can be used as protecting ligands for M6E8L6 clusters.
Organic polycarboxylates that exhibit high designability and stability are fundamental building units for constructing coordination and hydrogen-bonded frameworks in supramolecular chemistry. Recently, discrete metal complexes with noncoordinating carboxy moieties (Metal-Organic Carboxylates or Metal-Organic Carboxylic acids; MOCs) have attracted increasing attention as alternatives to organic carboxylates because of their simple synthetic procedures and structural diversity, as well as the ease of installing transition metal centers to provide molecular functionalities. This review provides an overview of multitopic MOCs with six or more noncoordinating carboxy groups, which are constructed via coordination of organic ligands with carboxylates to appropriate metal ions. The MOCs are classified by the type of donating elements present in the organic ligands employed, and their synthetic approaches and molecular and supramolecular structures are described. Of more than 100 multitopic MOCs described herein, 27 MOCs were used as the pre-prepared metalloligand for constructing metal–organic frameworks or coordination polymers. Such MOCs are stable in solution due to the chelate effect of the ligand motifs or the large ligand field stabilization energy of specific metal ions. Moreover, due to their high hydrophilicity, multitopic MOCs are available for biological applications and adsorption of hydrophilic molecules.
The difference of uranyl (UO<inf>2</inf>2+) complexes with Nitrilotri–3–propanoic acid and Tris(2–carboxyethyl) phosphine: N–tricarboxylate versus P–tricarboxylate
2022, Inorganica Chimica Acta
Citation Excerpt :
Crystal structures of TCEP complexes with Zn(II) [22,23], Cd(II) [22], Co(II)/(III) [24–26], Pt(II) [27–29], Pd(II) [30], Fe(I) [31], Au(I) [32], Rh(III) [33], and Ir(III) [33] were determined by X–ray diffraction. In almost of these compounds, TCEP was coordinated by P atom and carboxylate groups (COO–) [22–24,26,30] except of Pt(II) [28], Rh(III)[33], Ir(III) [33], Fe(I) [31], Au(I) [32], and Co(II) [25] complexes. Metal ions in those complexes were only coordinated by P atoms.
Nitrilotri–3–propanoic Acid (NTPA) and Tris(2–carboxyethyl) phosphine (TCEP) possess similar skeleton. This pair of isostructural ligands is a perfect set to assess the differences of uranyl (UO₂²⁺) complexes with N–tricarboxylate versus P–tricarboxylate. The protonation reactions of NTPA and TCEP were investigated by potentiometry and calorimetry. Complexation of uranyl with the both ligands was studied by potentiometry and structural analysis. The results indicate that central trialkylamine in NTPA has a higher affinity for the proton than trialkylphosphine in TCEP. Crystal structures and NMR analyses indicate that central amine of NTPA and central phosphine of TCEP are not involved in the bonding. NTPA/UO₂²⁺ complex is more stable than TCEP/UO₂²⁺ complex. This difference cannot be explained by electronic effect of central N and P atoms because of nonbonding interactions. The higher stability of UO₂²⁺/NTPA versus UO₂²⁺/TCEP may be due to the fact that the central N atom of NTPA has a lower steric hindrance than the central P atom of TCEP. Another possible reason is that UO₂²⁺/TCEP complexes have different coordination modes from UO₂²⁺/NTPA complexes.
Glutathione and H<inf>2</inf>O<inf>2</inf> consumption promoted photodynamic and chemotherapy based on biodegradable MnO<inf>2</inf>–Pt@Au<inf>25</inf> nanosheets
2019, Chemical Engineering Journal
Citation Excerpt :
Pt(IV) compounds as prodrugs have been widely applied in clinical treatment benefiting from their lower toxic than Pt(II) drugs [61,62]. Notably, Pt(IV) prodrugs can be reduced to higher toxic Pt(II) and result in dual–dissipation of GSH in the tum or microenvironment, improving the effect of chemotherapy and PDT [63–65]. Nowadays, although several carriers have been reported for carrying Pt-based drugs, the carrier with functional properties especially targeting and degradability is still scarce.
Photodynamic therapy (PDT) has become a significant anticancer method by making full use of reactive oxygen species (ROS) to kill cancer cells. However, high concentration of reductive glutathione (GSH) in tumor site is an enemy, which can decrease the PDT efficacy due to ROS consumption property of reductive GSH. To overcome the problem, here we design an innovative nanoplatform, which could integrate PDT, chemotherapy and magnetic resonance imaging (MRI) in one nanosystem. In this platform, MnO₂ nanosheets were employed as the carrier by conjugating photosensitizer (Au₂₅ nanoclusters) with platinum(IV) (Pt(IV)) prodrugs for synergistic PDT and chemotherapy. Interestingly, GSH can reduce MnO₂ nanosheets and Pt(IV) prodrugs simultaneously. Consequently, the concentration of intercellular GSH has been greatly decreased. More importantly, Mn²⁺ reduced from MnO₂ nanosheets remarkably improves both T₁– and T₂–weighted MRI owing to high level of GSH and H₂O₂ in acidic tumor microenvironment, and Pt(II) reduced from Pt(IV) gives rise to high chemotoxicity to cancer cells. Combined with high PDT efficiency by consuming large amount of intercellular GSH, this nanoplatform has successfully achieved the MRI guided synergistic therapy, which is promising for potential clinic applications in cancer therapy.
Linear gold(I) complex with tris-(2-carboxyethyl)phosphine (TCEP): Selective antitumor activity and inertness toward sulfur proteins
2018, Journal of Inorganic Biochemistry
The search for modulating ligand substitution reaction in gold complexes is essential to find new active metallo compounds for medical applications. In this work, a new linear and hydrosoluble gold^I complex with tris-(2-carboxyethylphosphine) (AuTCEP). The two phosphines coordinate linearly to the metal as solved by single crystal X-ray diffraction. Complete spectroscopic characterization is also reported. In vitro growth inhibition (GI₅₀) in a panel of nine tumorigenic and one non-tumorigenic cell lines demonstrated the complex is highly selective to ovarium adenocarcinoma (OVCAR-03) with GI₅₀ of 3.04 nmol mL⁻¹. Moreover, non-differential uptake of AuTCEP was observed between OVCAR-03 (tumor) and HaCaT (non-tumor) two cell lines. Biophysical evaluation with the sulfur-rich biomolecules showed the compound does not interact with two types of zinc fingers, bovine serum albumin, N-acetyl-l-cysteine and also l-histidine, revealing to be inert to ligand substitution reactions with these molecules. However, AuTCEP demonstrated to cleave plasmidial DNA, suggesting DNA as a possible target. No antibacterial activity was observed in the strains evaluated. Besides, it inhibits 15% of the activity of a mixture of serine-β-lactamase and metallo-β-lactamase from Bacillus cereus in the enzymatic activity assay, similarly to EDTA. These results suggest AuTCEP is selective to metallo-β-lactamase but the cell uptake is hindered, and the compound does not reach the periplasmic space of Gram-positive bacteria. The unique inert behavior of AuTCEP is interesting and represent the modulation of the reactivity through coordination chemistry to decrease the toxicity associated with Au^I complexes and its lack of specificity, generating very selective compounds with unexpected targets.
Exploring intein inhibition by platinum compounds as an antimicrobial strategy
2016, Journal of Biological Chemistry
Inteins, self-splicing protein elements, interrupt genes and proteins in many microbes, including the human pathogen Mycobacterium tuberculosis. Using conserved catalytic nucleophiles at their N- and C-terminal splice junctions, inteins are able to excise out of precursor polypeptides. The splicing of the intein in the mycobacterial recombinase RecA is specifically inhibited by the widely used cancer therapeutic cisplatin, cis-[Pt(NH₃)₂Cl₂], and this compound inhibits mycobacterial growth. Mass spectrometric and crystallographic studies of Pt(II) binding to the RecA intein revealed a complex in which two platinum atoms bind at N- and C-terminal catalytic cysteine residues. Kinetic analyses of NMR spectroscopic data support a two-step binding mechanism in which a Pt(II) first rapidly interacts reversibly at the N terminus followed by a slower, first order irreversible binding event involving both the N and C termini. Notably, the ligands of Pt(II) compounds that are required for chemotherapeutic efficacy and toxicity are no longer bound to the metal atom in the intein adduct. The lack of ammine ligands and need for phosphine represent a springboard for future design of platinum-based compounds targeting inteins. Because the intein splicing mechanism is conserved across a range of pathogenic microbes, developing these drugs could lead to novel, broad range antimicrobial agents.

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Journal of Organometallic Chemistry

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials and physical measurements

Properties and structures of compounds in solid state

Conclusions

References (36)

Coord. Chem. Rev.

Coord. Chem. Rev.

J. Inorg. Biochem.

Polyhedron

Anal. Biochem.

J. Am. Soc. Mass Spectrom.

Polyhedron

Inorg. Chim. Acta

Talanta

J. Biol. Chem.

J. Organometal. Chem.

Dalton Trans.

Recent Pat. Anti-Cancer Drug Discov.

Platinum-Based Drugs

Nature

J. Med. Chem.

J. Chem. Soc. Dalton Trans.

J. Organometal. Chem.

Cited by (14)

Reactivity of Ni<sup>II</sup>, Pd<sup>II</sup> and Pt<sup>II</sup> complexes bearing phosphine ligands towards Zn<sup>II</sup> displacement and hydrolysis in Cis<inf>2</inf>His<inf>2</inf> and Cis<inf>3</inf>His zinc-fingers domains

Multitopic metal–organic carboxylates available as supramolecular building units

The difference of uranyl (UO<inf>2</inf><sup>2+</sup>) complexes with Nitrilotri–3–propanoic acid and Tris(2–carboxyethyl) phosphine: N–tricarboxylate versus P–tricarboxylate

Glutathione and H<inf>2</inf>O<inf>2</inf> consumption promoted photodynamic and chemotherapy based on biodegradable MnO<inf>2</inf>–Pt@Au<inf>25</inf> nanosheets

Linear gold(I) complex with tris-(2-carboxyethyl)phosphine (TCEP): Selective antitumor activity and inertness toward sulfur proteins

Exploring intein inhibition by platinum compounds as an antimicrobial strategy